Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Seattle, WA: University of Washington, Seattle; 1993-. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. It is passed through families in a autosomal dominant fashion. Individuals with HANAC syndrome also experience a variety of eye problems. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Bookshelf 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. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 2009 Jun 25 [Updated 2016 Jul 7]. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. 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. A diagnosis can be confirmed through molecular genetic testing. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. (2007) 357:268795. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Washington, DC 20036 Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. 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). Federal government websites often end in .gov or .mil. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. His bedside manner was incredible. and transmitted securely. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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. 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. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. 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. COL4A1/A2-related disorders are dominant genetic disorders. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Ann Neurol. 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. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. ACS Omega. Summary: (2010). Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Probands' father had severe hypermetropia and bilateral cataracts. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Suite 310 This page is currently unavailable. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. N Engl J Med. 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/. 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. Painful muscle cramps can occur and can develop before three years of age. FOIA Bull Acad Natl Med. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Neurology. NORD strives to open new assistance programs as funding allows. Phone: 202-588-5700. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 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. Figure 3. Would you like email updates of new search results? 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. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. 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. I cannot describe the feeling of seeing your child healed. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. 2008 May;192(5):971-84; discussion 984-6. COL4A1 Syndrome CADASIL 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. Therapies are based on the specific symptoms in each individual. Hum Mol Genet. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. 11:827. doi: 10.3389/fneur.2020.00827. National Center for Biotechnology Information. The information on this site should not be used as a substitute for professional medical care or advice. doi: 10.1038/nmeth.2890, 22. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. (2020). Bennett RL, French KS, Resta RG, Doyle DL. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. doi: 10.1111/cge.12379, 13. II-2 had a limp since childhood attributed to forceps delivery. small vessel disease: a systematic review. 2012;21:R97-R110. Copyright 2023 by Gould Syndrome Foundation -. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 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. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Accessibility Bethesda, MD 20894, Web Policies This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. (2012) 54:56974. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. 128:4839. NORD is a registered 501(c)(3) charity organization. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Quincy, MA 02169 (19). Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 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. (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). Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. 30. Firstly, it segregates within the family with the phenotype. In the human genome, there are 46 chromosomes. This is called genotype-phenotype correlation. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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.