Science. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. HHS Vulnerability Disclosure, Help The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. It affects mainly young adults, children and more typically neonates. Epub 2016 Apr 24. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 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. Internet. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. . In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Before Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. 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). 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. Cephalic Disorders Fact Sheet. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. 1900 Crown Colony Drive PS: wrote thi paper and performed the review of the literature under the supervision of GN. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Childhood presentation of COL4A1 mutations. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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. At least 50 individuals with this condition have been described in the scientific literature. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Neurology. 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. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. eCollection 2022. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) How can gene variants affect health and development? In most cases, an affected person has one parent with the condition. 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. Phone: 202-588-5700. Ophthalmological features associated with COL4A1 mutations. Last updated: When we didnt feel we had any options left for treatment, All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Clin Genet. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Suite 310 To use the sharing features on this page, please enable JavaScript. Careers. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). The severity of the condition varies greatly among affected individuals. Fetal intracerebral hemorrhage and cataract: think COL4A1. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Copyright 2023 by Gould Syndrome Foundation -. Jeanne M, Gould DB. (2015) 17:40524. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. percent confident in Dr. Madsen and the epilepsy team. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Dev Med Child Neurol. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. 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). Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Epub 2022 Apr 14. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 Type IV collagen molecules attach to each other to form complex protein networks. doi: COL4A1 Syndrome CADASIL Teaching families how to advocate for their loved ones and access medical information. 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). A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. The retina is the light-sensitive membrane that lines the inside of the eyes. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. It is important to discuss these concepts with a genetic counselor and understand their implications. for the triple helical CB3[IV] domain. J Neurol Sci. COL4A1/A2-related disorders are dominant genetic disorders. 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. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). I cannot describe the feeling of seeing your child healed. 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. What are the different ways a genetic condition can be inherited? National Library of Medicine Quincy, MA 02169 Therapies are based on the specific symptoms in each individual. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Neurology. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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). Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Pediatr Neurol. Progressive cerebral atrophies in three children with COL4A1 mutations. Autosomal Dominant Brain Small Vessel Disease. 2009 Jun 25 [Updated 2016 Jul 7]. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. All authors contributed to the article and approved the submitted version. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. The size and location of cerebral cavities contributes to clinical variability. 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: Unable to load your collection due to an error, Unable to load your delegates due to an error. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. sharing sensitive information, make sure youre on a federal Various muscles can be affected and muscle strength can become weakened. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Childhood presentation of COL4A1 mutations. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. doi: 10.1007/s10897-008-9169-9, 16. Graefe's Arch Clin Exp Ophthalmol. 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. (2004) 62:16135. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Clipboard, Search History, and several other advanced features are temporarily unavailable. Neurology. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Changing lives of those with rare disease. 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. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 2010;17(13):1317-24. doi: During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. 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. He also wanted to remove a shunt that was implanted in When these ropes are secreted, they assemble into net-like structures outside the cells. 2010 Aug;41(8):e513-8. Axenfeld-Rieger anomaly and cataract can cause impaired vision. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. 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. 55 Kenosia Avenue Still other individuals may not develop any symptoms until well into adulthood.