Various treatments have been reported in the medical literature as part of single case reports or small series of patients. 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. Nearly half of these participants were diagnosed with infantile spasms. doi: 10.1212/01.WNL.0000123113.46672.68, 25. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. percent confident in Dr. Madsen and the epilepsy team. She, then, developed seizures which were controlled by valproic acid. The disorder causes many symptoms, not the least of which are strokes and epilepsy. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. An official website of the United States government. Autosomal Dominant Familial Porencephaly Type I. 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. Arch Neurol. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. 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. 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. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Clin Genet. Dev Med Child Neurol. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Fax: 203-263-9938, Washington, DC Office Changing lives of those with rare disease. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. 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. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. What is the prognosis of a genetic condition? doi: 10.1055/s-0031-1275343, 24. doi: 10.1002/ana.23736, 4. Teaching families how to advocate for their loved ones and access medical information. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. MedlinePlus also links to health information from non-government Web sites. Danbury, CT 06810 Please enable it to take advantage of the complete set of features! Summary. Agenesis of the Corpus Callosum | National Institute of Neurological Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Figure 3. (2009) 73:187382. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. small vessel disease: a systematic review. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Seattle, WA: University of Washington, Seattle; 1993-. 10.2174/092986710790936293. doi: 10.1212/WNL.0000000000001309, 8. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). 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. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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 COL4A1/A2-related disorders are believed to affect females and males in equal numbers. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. COL4A1-related brain small-vessel disease - MedlinePlus (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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. Careers. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. It looks like nothing was found at this location. 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. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. He would separate the two halves of her brain by 1779 Massachusetts Avenue During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. What are the different ways a genetic condition can be inherited? Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Affected individuals may have no observable symptoms or only isolated migraines with aura. (18) and Staals et al. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. cutting tissue called the corpus callosum, then make some additional delicate Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Understanding what it has taken to get her to this point, though, is close to unimaginable. N Engl J Med. The disorder causes many symptoms, not the least of which are strokes and epilepsy. doi: 10.1212/WNL.0b013e3181eee440, 28. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Antiinflammatory therapy with canakinumab for atherosclerotic disease. (1982) 40:5679. Internet. Clipboard, Search History, and several other advanced features are temporarily unavailable. Changing lives of those with rare disease. Graefe's Arch Clin Exp Ophthalmol. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Neurol. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. government site. 2009 Jun 25 [Updated 2016 Jul 7]. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. doi: 10.1007/s10897-008-9169-9, 16. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Stroke. doi: 10.1007/s00417-014-2800-6, 12. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. In most people, small vessel disease in the brain does not cause symptoms. (2006) 43:4905. (2015) 88:46873. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. doi: 10.1056/NEJMoa071906, 14. (2013) 73:4857. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Epub 2014 Jan 5. Dr. Madsen suggested Zeeva have an operation called a IV-3 was diagnosed with ventriculomegaly in utero. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. HANAC syndrome is a rare condition, although the exact prevalence is unknown. What does it mean if a disorder seems to run in my family? 1A-B). (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). 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. She also showed severe hypermetropia. If either parent also carries the mutation, it is considered inherited. Maybe try a search? It affects mainly young adults, children and more typically neonates. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. (2020). 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. 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 . Surgery may be necessary for individuals with severe cataracts. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. (2014) 83:122834. This is called genotype-phenotype correlation. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. 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. He also wanted to remove a shunt that was implanted in Pathology. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. (2007) 357:268795. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. The COL4A1 stroke syndrome. Neurology. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. The first time he came to meet us, Zeeva threw a sock at him. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare 2011 J Med Genet. People with HANAC syndrome develop kidney disease (nephropathy). Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. NCI CPTC Antibody Characterization Program. What is Gould Syndrome? - Gould Syndrome Foundation In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). (2002) 112:198202. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Ann Neurol. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Am J Med Genet. Clinical Testing and Workup In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Disclaimer. COL4A1 brain small-vessel disease - Radiopaedia INTERNET doi: 10.1212/WNL.0000000000000837, 20. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and 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. 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. There are no standardized treatment protocols or guidelines for affected individuals. Zagaglia Selch C, Nisevic JR, et al. Please note that NORD provides this information for the benefit of the rare disease community. Collagen, type IV, alpha 1 - Wikipedia But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. 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). The .gov means its official. eCollection 2022. Probands' father had severe hypermetropia and bilateral cataracts. 11:827. doi: 10.3389/fneur.2020.00827. Neurologic phenotypes associated with COL4A1/2 mutations Further refinement of COL4A1 and COL4A2 related cortical malformations. I cannot describe the feeling of seeing your child healed. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Copyright 2023 by Gould Syndrome Foundation -. Neurology. cuts under the microscope. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. 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. What are the different ways a genetic condition can be inherited? 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. 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. September 2003. At least 50 individuals with this condition have been described in the scientific literature. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Am J Neuroradiol. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. 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. 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/. 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. What does it mean to have a COL4A1 - Little Braveheart | Facebook Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). (2006) 354:148996. However, there are exceptions that depend on precisely when and where the mutation arose. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. When these ropes are secreted, they assemble into net-like structures outside the cells. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). 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). Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Purpose of review: 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. He was confident this would reduce or stop the 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. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. FOIA doi: 10.1111/cge.12379, 13. The COL4A1 and COL4A2 genes were screened in proband IV-6. Neurology. 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 Recent findings: (2017) 377:111931. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. 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). Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes.

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