Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Genet Med. (No doctor had ever taken a call on their lunch break to speak with me). She, then, developed seizures which were controlled by valproic acid. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 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. 1A-B). She has regular physical, speech, and occupational therapy. (1987) 8:4216. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 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. Danbury, CT 06810 As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. When this enzyme is elevated, it is a sign of muscle damage. 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. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. Stroke is a leading cause of death and serious long-term disability in developed nations. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Hereditary cerebral small vessel diseases: a review. (2004) 62:16135. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. 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). People with COL4A1-related brain small vessel disease 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). 1. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. 8600 Rockville Pike The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). (2007) 357:268795. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. In the brain, intracerebral hemorrhage is the most frequent phenotype. No use, distribution or reproduction is permitted which does not comply with these terms. All authors contributed to the article and approved the submitted version. How are genetic conditions treated or managed? Nat Methods. Clinical Testing and Workup Further refinement of COL4A1 and COL4A2 related cortical malformations. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Plaisier E, Ronco P. COL4A1-Related Disorders. 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). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. (2010). Treatment doi: 10.1038/jp.2013.135, 29. COL4A1 is an essential component for basal membrane stability. In people with HANAC syndrome, angiopathy affects several parts of the body. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Dev Med Child Neurol. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Facebook: https://www.facebook.com/Col4A1Foundation Please Note A dashed arrow indicates secondary atrophy in the left cerebral peduncle. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Individuals with HANAC syndrome also experience a variety of eye problems. doi: 10.1056/NEJMoa071906, 14. 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. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Summary. Clipboard, Search History, and several other advanced features are temporarily unavailable. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. official website and that any information you provide is encrypted Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. doi: 10.1002/ajmg.10452, 18. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Various muscles can be affected and muscle strength can become weakened. It looks like nothing was found at this location. Stroke. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Epub 2016 Apr 24. INTERNET Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. They are typically 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. 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. ClinVar; [VCV000389182.3]. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. At least 50 individuals with this condition have been described in the scientific literature. Painful muscle cramps can occur and can develop before three years of age. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. GeneReviews. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. NORD is a registered 501(c)(3) charity organization. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Neurol. doi: 10.1007/s10897-008-9169-9, 16. 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. Clin Genet. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. 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. HANAC syndrome is a rare condition, although the exact prevalence is unknown. National Institute of Neurological Disorders and Stroke. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). 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. Phone: 202-588-5700. Neurology. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. It is passed through families in a autosomal dominant fashion. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). The site is secure. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. doi: 10.1186/s12881-014-0097-2, 11. Still other individuals may not develop any symptoms until well into adulthood. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. HHS Vulnerability Disclosure, Help Neurology. 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. government site. In the human genome, there are 46 chromosomes. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Arch Ophthalmol. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. He smiled, caught it, and asked Zeeva if he could throw it back. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Neurology. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. It is important to discuss these concepts with a genetic counselor and understand their implications. National Center for Biotechnology Information. 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 For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Some individuals develop cysts on the kidney. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Standardized (15) familiar pedigree is showed in Figure 1. 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. The retina is the light-sensitive membrane that lines the inside of the eyes. To use the sharing features on this page, please enable JavaScript. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Autosomal Dominant Brain Small Vessel Disease. We provide education, advocacy, and resources for families and individuals 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. N Engl J Med. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Washington, DC 20036 Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Phone: 203-263-9938 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). Summary: 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 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). Hum Mol Genet. 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. (2010) 75:7479. 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. Lenses corrected for hypermetropia. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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. functional hemispherectomy. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 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). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Curr Opin Neurol. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. (1982) 40:5679. Please note that NORD provides this information for the benefit of the rare disease community. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Cereb Circ Cogn Behav. His bedside manner was incredible. Doctors and researchers to bring research and medical therapeutic options to those affected. Before It affects mainly young adults, children and more typically neonates. Copyright 2023 by Gould Syndrome Foundation -. 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. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. In most cases, an affected person has one parent with the condition. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. (2009) 73:187382. doi: 10.1007/s00417-014-2800-6, 12. COL4A1 and COL4A2 are on Chr. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 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.