MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. When we didnt feel we had any options left for treatment, COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. doi: 10.2214/ajr.149.2.351, 19. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). seizure activity. Internet. sharing sensitive information, make sure youre on a federal cutting tissue called the corpus callosum, then make some additional delicate Your support helps to ensure everyones free access to NORDs rare disease reports. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. 11:827. doi: 10.3389/fneur.2020.00827. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. N Engl J Med. However, there are exceptions that depend on precisely when and where the mutation arose. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Genet Med. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 1. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Arch Neurol. This group rarely survives beyond 2 years. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. doi: 10.1126/science.1109418, 5. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Firstly, it segregates within the family with the phenotype. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. He smiled, caught it, and asked Zeeva if he could throw it back. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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. 2010 Aug;41(8):e513-8. 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). Pediatr Neurol. 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. What is the prognosis of a genetic condition? Federal government websites often end in .gov or .mil. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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 Type IV collagen molecules attach to each other to form complex protein networks. Bookshelf In the brain, intracerebral hemorrhage is the most frequent phenotype. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Phone: 202-588-5700. Some individuals develop cysts on the kidney. Neurol. 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). Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. eCollection 2022 Nov 8. 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: doi: 10.1212/01.WNL.0000123113.46672.68, 25. Danbury, CT 06810 This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. mutations: a novel genetic multisystem disease. Neurology. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. (1987) 8:4216. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Summary. What are the different ways a genetic condition can be inherited? III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Fetal intracerebral hemorrhage and cataract: think COL4A1. Genet Med. 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. The information on this site should not be used as a substitute for professional medical care or advice. Eur J Med Genet. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. 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. 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). Stroke. How can gene variants affect health and development? This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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. Am J Med Genet. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. How are genetic conditions treated or managed? Treatment 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. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. The severity of the condition varies greatly among affected individuals. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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. (2008) 23:17. Congenital Cephalic Disorders 30. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. NCI CPTC Antibody Characterization Program. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. Unable to load your collection due to an error, Unable to load your delegates due to an error. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. J Med Genet. Copyright 2023 by Gould Syndrome Foundation -. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 55 Kenosia Avenue Neurology. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. In people with HANAC syndrome, angiopathy affects several parts of the body. (2010) 75:7479. What does it mean if a disorder seems to run in my family? In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. No microbleeds or cystic cavities were found. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. doi: 10.1007/s00417-014-2800-6, 12. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. doi: 10.1212/WNL.0000000000001309, 8. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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/. Curr Med Chem. Pathology. Suite 310 2011 Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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). (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). (2004) 62:16135. Bennett RL, French KS, Resta RG, Doyle DL. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Fax: 203-263-9938, Washington, DC Office (2014) 34:757. The COL4A1 stroke syndrome. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. 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.