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. HANAC syndrome is caused by genetic changes in the COL4A1 gene. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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. How can gene variants affect health and development? I cannot describe the feeling of seeing your child healed. 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. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 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. COL4A1/A2-related disorders are dominant genetic disorders. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Resource(s) for Medical Professionals and Scientists on This Disease: Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 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. Cereb Circ Cogn Behav. 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. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Curr Opin Neurol. The .gov means its official. (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). (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Lanfranconi S, Markus HS. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. 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. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . HANAC syndrome is a rare condition, although the exact prevalence is unknown. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 10.1161/STROKEAHA.110.581918. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. doi: 10.1001/archophthalmol.2010.42, 10. The site is secure. cutting tissue called the corpus callosum, then make some additional delicate How are genetic conditions treated or managed? III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. TTY: (866) 411-1010 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. All authors contributed to the article and approved the submitted version. Stroke. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 11:827. doi: 10.3389/fneur.2020.00827. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. 1900 Crown Colony Drive (2020). 1779 Massachusetts Avenue After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. IV-3 was diagnosed with ventriculomegaly in utero. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. 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 . PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Zeevas brain to treat a cyst in her brain caused by porencephaly. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. doi: Curr Opin Neurol. Matrix Biol. Neurology. Berg R, Aleck A, Kaplan A. Familial porencephaly. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Dev Med Child Neurol. Unable to load your collection due to an error, Unable to load your delegates due to an error. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 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). 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. II-2 had a limp since childhood attributed to forceps delivery. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe 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. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Your support helps to ensure everyones free access to NORDs rare disease reports. Neurology. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. It is passed through families in a autosomal dominant fashion. 2008 May;192(5):971-84; discussion 984-6. It is not uncommon for an unaffected parent to have a severely affected child. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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 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. She has regular physical, speech, and occupational therapy. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. (2002) 112:198202. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. 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). 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. Front. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. J Genet Couns. can also contribute. 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. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Eur J Paediatr Neurol. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Curr Med Chem. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. COL4A1 and COL4A2 are on Chr. What are the different ways a genetic condition can be inherited? Phone: 617-249-7300, Danbury, CT office Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. No use, distribution or reproduction is permitted which does not comply with these terms. When this enzyme is elevated, it is a sign of muscle damage. September 2003. (2005) 308:116771. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. (2015) 88:46873. (2013) 73:4857. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 2009 Jun 25 [updated 2016 Jul 7]. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Quincy, MA 02169 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. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Bookshelf Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Suite 310 Nearly half of these participants were diagnosed with infantile spasms. Contact a health care provider if you have questions about your health. 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. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. seizure activity. 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. 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). Ann Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. my mom suggested we call Boston Childrens Hospital. What does it mean if a disorder seems to run in my family? (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (1987) 8:4216. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Gould Syndrome is a rare, genetic, multi-system disorder. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. ACS Omega. 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.0000000000000837, 20. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Would you like email updates of new search results? This condition causes mutations in genes that produce a specific type of collagen. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. 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. At least six affected families have been described in the scientific literature. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Hum Mol Genet. 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. Axenfeld-Rieger anomaly and cataract can cause impaired vision. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. BMC Med Genet. In the brain, intracerebral hemorrhage is the most frequent phenotype. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. small vessel disease: a systematic review. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. doi: 10.1038/nmeth.2890, 22. Please note that NORD provides this information for the benefit of the rare disease community. It affects mainly young adults, children and more typically neonates. Accessibility doi: 10.1136/jmg.2005.035584, 15. Epub 2010 Jun 17. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. He also wanted to remove a shunt that was implanted in COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 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. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Changing lives of those with rare disease. doi: 10.1001/archneur.1983.04050080067013, 17. MeSH Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Genet Med. Doctors and researchers to bring research and medical therapeutic options to those affected. 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). When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Bethesda, MD 20894, Web Policies https://www.ncbi.nlm.nih.gov/pubmed/26610912. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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. Bone. 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 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). The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. doi: 10.1212/WNL.0000000000001309, 8. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . 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). NORD strives to open new assistance programs as funding allows. Matrix Biol. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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. 2009 Jun 25 [Updated 2016 Jul 7]. The retina is the light-sensitive membrane that lines the inside of the eyes. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. 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). Disclaimer. If either parent also carries the mutation, it is considered inherited. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Neurology. Pediatr Neurol. Standardized (15) familiar pedigree is showed in Figure 1. (2012) 54:56974. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. GeneReviews. To use the sharing features on this page, please enable JavaScript. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. (19). (2010) 75:7479. 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. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. 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. Early intervention is important in ensuring that children with reach their highest potential. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Neurol. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The first time he came to meet us, Zeeva threw a sock at him. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Maybe try a search? Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction.
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