More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Ann Clin Neurol Neurosurg. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (2015) 17:84353. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. 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. Neurol. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. The risk is the same for males and females. II-2 had a limp since childhood attributed to forceps delivery. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. mutations: a novel genetic multisystem disease. doi: 10.2214/ajr.149.2.351, 19. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Suite 500 Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Dr. Madsen suggested Zeeva have an operation called a Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. She, then, developed seizures which were controlled by valproic acid. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. In the brain, intracerebral hemorrhage is the most frequent phenotype. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. The site is secure. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. doi: 10.1007/s00417-014-2800-6, 12. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. He also wanted to remove a shunt that was implanted in 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. To use the sharing features on this page, please enable JavaScript. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Genet Med. doi: 10.1056/NEJMoa1707914, 6. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 55 Kenosia Avenue NORD strives to open new assistance programs as funding allows. People with HANAC syndrome develop kidney disease (nephropathy). Congenital Cephalic Disorders Quincy, MA 02169 Purpose of review: What does it mean if a disorder seems to run in my family? The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Dev Med Child Neurol. 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. September 2003. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. 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. Neurology. 2018;91:e2078-e2088. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. (2012) 54:56974. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Clinical Testing and Workup Curr Opin Neurol. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Neurology. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. When this enzyme is elevated, it is a sign of muscle damage. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. There are no standardized treatment protocols or guidelines for affected individuals. These genes are the blueprints for two proteins that wind together like a long rope inside cells. (2014) 83:122834. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. 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). Phone: 202-588-5700. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. sharing sensitive information, make sure youre on a federal Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. PMC Changing lives of those with rare disease. doi: 10.1056/NEJMoa071906, 14. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Fetal intracerebral hemorrhage and cataract: think COL4A1. 2011 GeneReviews. 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. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. 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. The number of genes implicated in epilepsy has grown rapidly in the past decade. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 10.1161/STROKEAHA.110.581918. 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). Still other individuals may not develop any symptoms until well into adulthood. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Internet. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. doi: 10.1001/archophthalmol.2010.42, 10. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Careers. 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. Therapies are based on the specific symptoms in each individual. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. To use the sharing features on this page, please enable JavaScript. Am J Med Genet. (2010) 75:7479. This group rarely survives beyond 2 years. doi: 10.1212/WNL.0000000000001309, 8. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Nearly half of these participants were diagnosed with infantile spasms. 2008 May;192(5):971-84; discussion 984-6. 2011 This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. It is not uncommon for an unaffected parent to have a severely affected child. If we dont have a program for you now, please continue to check back with us. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. No microbleeds or cystic cavities were found. The .gov means its official. Arch Ophthalmol. The size and location of cerebral cavities contributes to clinical variability. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: Changing lives of those with rare disease. It is ubiquitously expressed in many tissues and cell types. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). Copyright 2023 by Gould Syndrome Foundation -. Neurology. Curr Med Chem. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. my mom suggested we call Boston Childrens Hospital. government site. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. It is important to discuss these concepts with a genetic counselor and understand their implications. 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. 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. COL4A1 Syndrome CADASIL The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 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). Childhood presentation of COL4A1 mutations. (2009) 73:187382. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Further refinement of COL4A1 and COL4A2 related cortical malformations. In people with HANAC syndrome, angiopathy affects several parts of the body. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Bethesda, MD 20894, Web Policies The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. seizure activity. (2005) 308:116771. Individuals with HANAC syndrome also experience a variety of eye problems. 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 doi: 10.1038/gim.2015.30, 21. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. doi: 10.1007/s10897-008-9169-9, 16. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Seattle, WA: University of Washington, Seattle; 1993-. These exceptions are nuanced and should be discussed with a genetic counselor. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. All authors contributed to the article and approved the submitted version. Bull Acad Natl Med. Epub 2010 Jun 17. Hereditary cerebral small vessel diseases: a review. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. (2017) 377:111931. Curr Opin Neurol. 2010;41:e513-518. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. (2014) 15:16. This site needs JavaScript to work properly. How can gene variants affect health and development? Neurol. In the human genome, there are 46 chromosomes. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Mutations in the COL4A1 gene cause HANAC syndrome. (No doctor had ever taken a call on their lunch break to speak with me). Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. came with risks and was the hardest decision we had ever faced, yet we felt 100 Please note that NORD provides this information for the benefit of the rare disease community. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Eur J Med Genet. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. 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. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Progressive cerebral atrophies in three children with COL4A1 mutations. 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). 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. (1982) 40:5679. How are genetic conditions treated or managed? Lanfranconi S, Markus HS. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. N Engl J Med. 1. 1A-B). Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (2014) 34:757. 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).