The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). MedlinePlus also links to health information from non-government Web sites. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. She also showed severe hypermetropia. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Curr Med Chem. Type IV collagen molecules attach to each other to form complex protein networks. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Phone: 203-263-9938 The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Genet Med. 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. How are genetic conditions treated or managed? I cannot describe the feeling of seeing your child healed. 1A-B). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Washington, DC 20036 What are the different ways a genetic condition can be inherited? COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. 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. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. (2015) 84:91826. mutations: a novel genetic multisystem disease. doi: 10.1001/archophthalmol.2010.42, 10. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Purpose of review: Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Neurol. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. COL4A1/A2-related disorders are dominant genetic disorders. 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. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Cephalic Disorders Fact Sheet. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Zeevas brain to treat a cyst in her brain caused by porencephaly. (2008) 17:42433. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. In the human genome, there are 46 chromosomes. In people with HANAC syndrome, angiopathy affects several parts of the body. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Further refinement of COL4A1 and COL4A2 related cortical malformations. What is the prognosis of a genetic condition? With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. 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). This condition causes mutations in genes that produce a specific type of collagen. 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. Curr Opin Neurol. HANAC syndrome is a rare condition, although the exact prevalence is unknown. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Federal government websites often end in .gov or .mil. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Pathology. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Bookshelf The site is secure. 1900 Crown Colony Drive He smiled, caught it, and asked Zeeva if he could throw it back. These exceptions are nuanced and should be discussed with a genetic counselor. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. At least six affected families have been described in the scientific literature. 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. Facebook: https://www.facebook.com/Col4A1Foundation Please Note https://www.ncbi.nlm.nih.gov/pubmed/26610912. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Science. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Bull Acad Natl Med. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. However, in people with HANAC syndrome, these aneurysms typically do not burst. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. INTERNET COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Jeanne M, Gould DB. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Migraines can occur with or without aura. (2017) 5758:2944. (2004) 62:16135. percent confident in Dr. Madsen and the epilepsy team. Congenital Cephalic Disorders Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. (2010). Zagaglia Selch C, Nisevic JR, et al. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. The COL4A1 and COL4A2 genes were screened in proband IV-6. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Childhood presentation of COL4A1 mutations. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Jeanne M, Gould DB. came with risks and was the hardest decision we had ever faced, yet we felt 100 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/. COL4A1 mutations as a monogenic cause of cerebral He also wanted to remove a shunt that was implanted in 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 These genes are the blueprints for two proteins that wind together like a long rope inside cells. 8600 Rockville Pike COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. 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. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Am J Med Genet A. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. Disclaimer. Dr. Madsen suggested Zeeva have an operation called a BMC Med Genet. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. We provide education, advocacy, and resources for families and individuals affected. Neuropediatrics. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Please enable it to take advantage of the complete set of features! functional hemispherectomy. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. eCollection 2022. Unauthorized use of these marks is strictly prohibited. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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. Suite 310 doi: 10.1038/gim.2014.210, 3. Suite 500 Antiinflammatory therapy with canakinumab for atherosclerotic disease. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Nat Methods. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. Suite 500 Painful muscle cramps can occur and can develop before three years of age. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 30. Matrix Biol. doi: 10.1038/jp.2013.135, 29. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. (2014) 15:16. NORD strives to open new assistance programs as funding allows. Last updated: The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. seizure activity. National Institute of Neurological Disorders and Stroke. (2020). Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Figure 3. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Please note that NORD provides this information for the benefit of the rare disease community. 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, . Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. 2018;61:765-772. (2017) 377:111931. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Eur J Paediatr Neurol. 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). About half of people with this condition 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). COL4A1 is an essential component for basal membrane stability. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. She, then, developed seizures which were controlled by valproic acid. There are no standardized treatment protocols or guidelines for affected individuals. 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. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Please note that NORD provides this information for the benefit of the rare disease community. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. can also contribute. Nearly half of these participants were diagnosed with infantile spasms. (2010) 14:1827. Front Aging Neurosci. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. He would separate the two halves of her brain by 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. It is ubiquitously expressed in many tissues and cell types. The severity of the condition varies greatly among affected individuals. eCollection 2022 Nov 8. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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. Ann Neurol. FOIA Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 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. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Six alpha chains of type IV. This is called genotype-phenotype correlation. (2014) 34:757. ACS Omega. (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).
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