This page is currently unavailable. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Standardized (15) familiar pedigree is showed in Figure 1. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). 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. . Neuropediatrics. 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. Neurology. How are genetic conditions treated or managed? Seattle, WA: University of Washington, Seattle; 1993-. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. In most cases, an affected person has one parent with the condition. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 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. 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. (2004) 62:16135. eCollection 2022 Nov 8. Neurology. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: Bookshelf View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. (2014) 11:3612. COL4A1/A2-related disorders are dominant genetic disorders. Gould Syndrome is an ultra rare genetic, multi-system disorder. She also showed severe hypermetropia. Would you like email updates of new search results? Internet. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 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. Disclaimer. Pediatr Neurol. 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). Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. The COL4A2 test was negative. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Clinical Testing and Workup Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Doctors and researchers to bring research and medical therapeutic options to those affected. 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. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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. Autosomal Dominant Familial Porencephaly Type I. Careers. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. doi: 10.1186/s12881-014-0097-2, 11. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 2009 Jun 25 [Updated 2016 Jul 7]. However, in people with HANAC syndrome, these aneurysms typically do not burst. 2010 Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Phone: 617-249-7300, Danbury, CT office It is passed through families in a autosomal dominant fashion. Migraines can occur with or without aura. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Bethesda, MD 20894, Web Policies This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Suite 500 Phone: 202-588-5700. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Before 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (2017) 5758:2944. government site. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 2008 May;192(5):971-84; discussion 984-6. 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. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Ann Neurol. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. She, then, developed seizures which were controlled by valproic acid. Stroke. 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. While there are other explanations, parental mosaicism should be considered. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. doi: 10.1212/WNL.0b013e3181c3fd12, 9. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. doi: 10.1007/s00417-014-2800-6, 12. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Please enable it to take advantage of the complete set of features! 30. Graefe's Arch Clin Exp Ophthalmol. 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. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. (2007) 357:268795. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Hereditary cerebral small vessel diseases: a review. doi: 10.1111/j.1469-8749.2011.04198.x, 26. It affects mainly young adults, children and more typically neonates. 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. The https:// ensures that you are connecting to the The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. (2008) 17:42433. (2015) 84:91826. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. In the brain, intracerebral hemorrhage is the most frequent phenotype. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. 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. Nearly half of these participants were diagnosed with infantile spasms. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. doi: 10.1212/WNL.0b013e3181eee440, 28. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. can also contribute. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. (2014) 15:16. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Accessibility With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. N Engl J Med. Am J Med Genet. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 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. 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). Ultrasound in utero from IV-6 (A). See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. eCollection 2022. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The COL4A1 stroke syndrome. Cereb Circ Cogn Behav. 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). People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 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. Firstly, it segregates within the family with the phenotype. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Dr. Madsen suggested Zeeva have an operation called a This is called genotype-phenotype correlation. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Front Aging Neurosci. To use the sharing features on this page, please enable JavaScript. 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). September 2003. Matrix Biol. What are the different ways a genetic condition can be inherited? HHS Vulnerability Disclosure, Help Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. This condition causes mutations in genes that produce a specific type of collagen. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Figure 3. 11:827. doi: 10.3389/fneur.2020.00827. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Genet Med. mutations: a novel genetic multisystem disease. (2009) 73:187382. 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. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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). PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 4 Both . The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Neurology. Lenses corrected for hypermetropia. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. (No doctor had ever taken a call on their lunch break to speak with me). 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. It is ubiquitously expressed in many tissues and cell types. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). cuts under the microscope. ClinVar; [VCV000389182.3]. Suite 500 Childhood presentation of COL4A1 mutations. 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. Unauthorized use of these marks is strictly prohibited. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. 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. (2015) 17:84353. 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). The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Contact a health care provider if you have questions about your health. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. 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. Quincy, MA 02169 Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Muscle cramps can be spontaneous or triggered by exercise. PS: wrote thi paper and performed the review of the literature under the supervision of GN. The signs and symptoms can manifest at almost any age from before birth to old age. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Changing lives of those with rare disease. The risk is the same for males and females. Federal government websites often end in .gov or .mil. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. His bedside manner was incredible. Changing lives of those with rare disease. Washington, DC 20036 Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Cavalin M, Mine M, Philbert M, et al. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Phone: 203-263-9938 (2013) 73:4857. sharing sensitive information, make sure youre on a federal Lanfranconi S, Markus HS. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. 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. (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-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. In the human genome, there are 46 chromosomes. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. However, there are exceptions that depend on precisely when and where the mutation arose. In people with HANAC syndrome, angiopathy affects several parts of the body. 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.