Quincy, MA 02169 Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Plaisier E, Ronco P. COL4A1-Related Disorders. The risk is the same for males and females. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. eCollection 2021. 128:4839. In the brain, intracerebral hemorrhage is the most frequent phenotype. The https:// ensures that you are connecting to the Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. 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). What is the prognosis of a genetic condition? 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 Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. 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. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. doi: 10.1212/WNL.0000000000000837, 20. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. At least 50 individuals with this condition have been described in the scientific literature. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. doi: 10.1001/archneur.1983.04050080067013, 17. The retina is the light-sensitive membrane that lines the inside of the eyes. If we dont have a program for you now, please continue to check back with us. Gould Syndrome is an ultra rare genetic, multi-system disorder. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. All authors contributed to the article and approved the submitted version. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. 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. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. This group rarely survives beyond 2 years. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Bull Acad Natl Med. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Axenfeld-Rieger anomaly and cataract can cause impaired vision. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Neurology. 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). Muscle cramps can be spontaneous or triggered by exercise. Zeevas brain to treat a cyst in her brain caused by porencephaly. There are no standardized treatment protocols or guidelines for affected individuals. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. The disorder causes many symptoms, not the least of which are strokes and epilepsy. The size and location of cerebral cavities contributes to clinical variability. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. He would separate the two halves of her brain by Stroke is a leading cause of death and serious long-term disability in developed nations. Matrix Biol. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Unable to load your collection due to an error, Unable to load your delegates due to an error. Childhood presentation of COL4A1 mutations. 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: Epub 2014 Jan 5. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. sharing sensitive information, make sure youre on a federal The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. doi: 10.1038/nmeth.2890, 22. 2010;17(13):1317-24. doi: Dev Med Child Neurol. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. She, then, developed seizures which were controlled by valproic acid. INTERNET The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. The COL4A1 and COL4A2 genes were screened in proband IV-6. In most cases, an affected person has one parent with the condition. What are the different ways a genetic condition can be inherited? COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. official website and that any information you provide is encrypted Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. National Institute of Neurological Disorders and Stroke. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Nearly half of these participants were diagnosed with infantile spasms. TTY: (866) 411-1010 When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. and transmitted securely. 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). Seattle, WA: University of Washington, Seattle; 1993-. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Gould Syndrome is an ultra rare genetic, multi-system disorder. 1900 Crown Colony Drive https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Mutations in the COL4A1 gene cause HANAC syndrome. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. NORD is a registered 501(c)(3) charity organization. His bedside manner was incredible. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 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). Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Doctors and researchers to bring research and medical therapeutic options to those affected. 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. 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/. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. The first time he came to meet us, Zeeva threw a sock at him. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Genet Med. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: It is not uncommon for an unaffected parent to have a severely affected child. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. doi: 10.1111/cge.12543. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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. Science. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). 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. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Stroke. 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. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Recent findings: Hum Mol Genet. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Unauthorized use of these marks is strictly prohibited. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. (2015) 88:46873. Jeanne M, Gould DB. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 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. Phone: 617-249-7300, Danbury, CT office Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. While there are other explanations, parental mosaicism should be considered. 1779 Massachusetts Avenue Am J Neuroradiol. These genes are the blueprints for two proteins that wind together like a long rope inside cells. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 1900 Crown Colony Drive Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). (1987) 8:4216. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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). Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Role of COL4A1 in small-vessel disease and hemorrhagic stroke. (2007) 357:268795. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. 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. 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). 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. 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). 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. People with HANAC syndrome develop kidney disease (nephropathy). Danbury, CT 06810 The COL4A1 stroke syndrome. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Bennett RL, French KS, Resta RG, Doyle DL. (2017) 5758:2944. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. ACS Omega. 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. (1982) 40:5679. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. doi: 10.1111/cge.12379, 13. (2004) 62:16135. No use, distribution or reproduction is permitted which does not comply with these terms. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. The information on this site should not be used as a substitute for professional medical care or advice. The information on this site should not be used as a substitute for professional medical care or advice. Autosomal Dominant Brain Small Vessel Disease. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). (2020). Lanfranconi S, Markus HS. Antiinflammatory therapy with canakinumab for atherosclerotic disease. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Nat Methods. 8600 Rockville Pike Probands' father had severe hypermetropia and bilateral cataracts. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. (2002) 112:198202. Genet Med. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Neurol. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Neurology. Stroke. Bookshelf Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). 55 Kenosia Avenue COL4A1/A2-related disorders are dominant genetic disorders. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Danbury, CT 06810 Ophthalmological features associated with COL4A1 mutations. doi: 10.1212/WNL.0000000000001309, 8. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Contact a health care provider if you have questions about your health. 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. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Type IV collagen molecules attach to each other to form complex protein networks. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. (No doctor had ever taken a call on their lunch break to speak with me). Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. If either parent also carries the mutation, it is considered inherited. 10.1161/STROKEAHA.110.581918. It affects mainly young adults, children and more typically neonates. 2008 May;192(5):971-84; discussion 984-6. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. doi: 10.1212/WNL.0b013e3181c3fd12, 9. (2014) 34:757. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. What are the different ways a genetic condition can be inherited? HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. government site. doi: 10.1016/j.matbio.2016.10.003, 23. Understanding what it has taken to get her to this point, though, is close to unimaginable. Changing lives of those with rare disease. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Clinical Testing and Workup We provide education, advocacy, and resources for families and individuals affected. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Epub 2022 Apr 14. NORD strives to open new assistance programs as funding allows. (2010) 14:1827. Autosomal Dominant Familial Porencephaly Type I. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 30. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules.