Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. COL4A1 mutations as a monogenic cause of cerebral (2014) 15:16. It is important to discuss these concepts with a genetic counselor and understand their implications. Plaisier E, Ronco P. COL4A1-Related Disorders. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Cavalin M, Mine M, Philbert M, 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 . This page is currently unavailable. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 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. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. government site. Ann Neurol. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Phone: 203-263-9938 PS: wrote thi paper and performed the review of the literature under the supervision of GN. Hum Mol Genet. (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). COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Neurology. Nearly half of these participants were diagnosed with infantile spasms. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. (1987) 8:4216. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. (2014) 252:178994. 2010 Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Quincy, MA 02169 In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. The risk is the same for males and females. Progressive cerebral atrophies in three children with COL4A1 mutations. What does it mean if a disorder seems to run in my family? Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). How can gene variants affect health and development? The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. NCI CPTC Antibody Characterization Program. 2009 Jun 25 [updated 2016 Jul 7]. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: doi: 10.1002/ajmg.10452, 18. 2011 doi: 10.1001/archophthalmol.2010.42, 10. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. (2011) 42:13. doi: 10.1111/cge.12543. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. January 31, 2019 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. Suite 500 Curr Opin Neurol. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. National Center for Biotechnology Information. The disorder causes many symptoms, not the least of which are strokes and epilepsy. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. doi: 10.1016/j.matbio.2016.10.003, 23. 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). 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. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. N Engl J Med. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 1. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. MeSH Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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). Danbury, CT 06810 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. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 2011 Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Dev Med Child Neurol. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Individuals with HANAC syndrome also experience a variety of eye problems. No microbleeds or cystic cavities were found. eCollection 2022. Doctors and researchers to bring research and medical therapeutic options to those affected. 2018;61:765-772. eCollection 2022 Nov 8. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Zeevas brain to treat a cyst in her brain caused by porencephaly. small vessel disease: a systematic review. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Jeanne M, Gould DB. These exceptions are nuanced and should be discussed with a genetic counselor. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. If either parent also carries the mutation, it is considered inherited. People listened to us and to Zeeva in a very different and proactive way. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Summary: Contact a health care provider if you have questions about your health. (2010) 14:1827. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). ACS Omega. Science. The COL4A1 and COL4A2 genes were screened in proband IV-6. Am J Med Genet A. seizure activity. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. J Neurol Sci. Firstly, it segregates within the family with the phenotype. doi: 10.1056/NEJMoa071906, 14. Cephalic Disorders Fact Sheet. 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. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. TTY: (866) 411-1010 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. In most cases, an affected person has one parent with the condition. It affects mainly young adults, children and more typically neonates. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Curr Opin Neurol. eCollection 2022. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. doi: 10.1212/WNL.0b013e3181eee440, 28. 1900 Crown Colony Drive Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Changing lives of those with rare disease. 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. doi: 10.1038/gim.2015.30, 21. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. National Institute of Neurological Disorders and Stroke. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Childhood presentation of COL4A1 mutations. Purpose of review: The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Unauthorized use of these marks is strictly prohibited. doi: 10.1111/j.1469-8749.2011.04198.x, 26. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Bull Acad Natl Med. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. (2012) 54:56974. Genet Med. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. It looks like nothing was found at this location. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 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). Bookshelf A diagnosis can be confirmed through molecular genetic testing. BMC Med Genet. What is the prognosis of a genetic condition? A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. I cannot describe the feeling of seeing your child healed. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Am J Neuroradiol. Muscle cramps can be spontaneous or triggered by exercise. 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. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. (2015) 17:40524. 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). PMC Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. Clin Neurol Neurosurg. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Bethesda, MD 20894, Web Policies Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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. 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. Arch Ophthalmol. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Gould Syndrome is a rare, genetic, multi-system disorder. At least six affected families have been described in the scientific literature. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Gould Syndrome is an ultra rare genetic, multi-system disorder. doi: 10.1186/s12881-014-0097-2, 11. mutations: a novel genetic multisystem disease. *Correspondence: Pasquale Scoppettuolo, [email protected], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). This site needs JavaScript to work properly. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. came with risks and was the hardest decision we had ever faced, yet we felt 100 A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). Autosomal Dominant Familial Porencephaly Type I. His bedside manner was incredible. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. This is called genotype-phenotype correlation. Some individuals develop cysts on the kidney. How are genetic conditions treated or managed? At least 50 individuals with this condition have been described in the scientific literature. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. 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. (2015) 17:84353. (2014) 11:3612. 55 Kenosia Avenue She also showed severe hypermetropia. Matrix Biol. doi: 10.1007/s00417-014-2800-6, 12. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Neuropediatrics. (2007) 357:268795. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Neurology. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 10.1161/STROKEAHA.110.581918. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). Epub 2016 Apr 24. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 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.