IV-3 and IV-6 are closely followed by a neuropediatrician (VW). The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. (2020). At least 50 individuals with this condition have been described in the scientific literature. IV-3 was diagnosed with ventriculomegaly in utero. Zagaglia Selch C, Nisevic JR, et al. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Federal government websites often end in .gov or .mil. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. National Institute of Neurological Disorders and Stroke. 2011 Jeanne M, Gould DB. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Neurology. Disease Overview. Epub 2022 Apr 14. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. January 31, 2019 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Purpose of review: doi: 10.1111/cge.12379, 13. 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. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Dev Med Child Neurol. eCollection 2021. 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). As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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). However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. (1987) 8:4216. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Muscle cramps can be spontaneous or triggered by exercise. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Bone. doi: 10.1212/WNL.0b013e3181c3fd12, 9. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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. 55 Kenosia Avenue 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. All authors contributed to the article and approved the submitted version. doi: 10.1002/ajmg.10452, 18. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Curr Med Chem. Ultrasound in utero from IV-6 (A). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. (2014) 11:3612. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Summary. However, in people with HANAC syndrome, these aneurysms typically do not burst. This condition causes mutations in genes that produce a specific type of collagen. Autosomal Dominant Brain Small Vessel Disease. She also showed severe hypermetropia. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Seattle, WA: University of Washington, Seattle; 1993-. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. How can gene variants affect health and development? Gould Syndrome is a rare, genetic, multi-system disorder. doi: 10.1212/WNL.0b013e3181eee440, 28. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Please enable it to take advantage of the complete set of features! BMC Med Genet. percent confident in Dr. Madsen and the epilepsy team. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 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. It is ubiquitously expressed in many tissues and cell types. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Quincy, MA 02169 View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 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). Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Berg R, Aleck A, Kaplan A. Familial porencephaly. 1A-B). The COL4A2 test was negative. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. He would separate the two halves of her brain by IV-3 goes to a normal school, but special schooling is required for IV-6. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. The https:// ensures that you are connecting to the FOIA Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. What are the different ways a genetic condition can be inherited? Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Genet Med. (2015) 17:40524. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. 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). When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Mutations in the COL4A1 gene cause HANAC syndrome. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Neurology. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Epub 2014 Jan 5. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Your support helps to ensure everyones free access to NORDs rare disease reports. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). PMC 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. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Neurology. doi: 10.1038/gim.2015.30, 21. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. doi: 10.1056/NEJMoa053727, 7. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 8600 Rockville Pike Would you like email updates of new search results? The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Dev Med Child Neurol. NORD strives to open new assistance programs as funding allows. Suite 310 Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Epub 2010 Jun 17. Ophthalmological features associated with COL4A1 mutations. It affects mainly young adults, children and more typically neonates. 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. Teaching families how to advocate for their loved ones and access medical information. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. The retina is the light-sensitive membrane that lines the inside of the eyes. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 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. 2011 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. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 11:827. doi: 10.3389/fneur.2020.00827. 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. 2010 Graefe's Arch Clin Exp Ophthalmol. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 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. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. 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. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Facebook: https://www.facebook.com/Col4A1Foundation Please Note The disorder causes many symptoms, not the least of which are strokes and epilepsy. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. seizure activity. 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. (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). Pediatr Neurol. Bull Acad Natl Med. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. (2018) 91:e207888. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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: During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. 1900 Crown Colony Drive 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. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Eur J Paediatr Neurol. Painful muscle cramps can occur and can develop before three years of age. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. The information on this site should not be used as a substitute for professional medical care or advice. These exceptions are nuanced and should be discussed with a genetic counselor. Nearly half of these participants were diagnosed with infantile spasms. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 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. 2010;41:e513-518. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. When this enzyme is elevated, it is a sign of muscle damage. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. COL4A1/A2-related disorders are dominant genetic disorders. Phone: 617-249-7300, Danbury, CT office (2011) 42:13. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. doi: 10.2214/ajr.149.2.351, 19. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. People listened to us and to Zeeva in a very different and proactive way. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 1900 Crown Colony Drive Migraines can occur with or without aura. (2010) 75:7479. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. cutting tissue called the corpus callosum, then make some additional delicate Summary: Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. mutations: a novel genetic multisystem disease. COL4A1 and COL4A2 are on Chr. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. If either parent also carries the mutation, it is considered inherited. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Recent findings: The information on this site should not be used as a substitute for professional medical care or advice. Surgery may be necessary for individuals with severe cataracts. Ann Neurol. doi: 10.1001/archneur.1983.04050080067013, 17. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. National Center for Biotechnology Information. official website and that any information you provide is encrypted Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Am J Med Genet. The severity of the condition varies greatly among affected individuals. 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. ACS Omega. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Neurology. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 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. 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. Arch Ophthalmol. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Am J Med Genet A. 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. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 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. and transmitted securely. Before my mom suggested we call Boston Childrens Hospital. 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. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. HANAC syndrome is caused by genetic changes in the COL4A1 gene. 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.
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