Pathology. 2008 May;192(5):971-84; discussion 984-6. 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). Please note that NORD provides this information for the benefit of the rare disease community. TTY: (866) 411-1010 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. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. (2006) 354:148996. 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 2010 Jun 17. Changing lives of those with rare disease. (No doctor had ever taken a call on their lunch break to speak with me). Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Understanding what it has taken to get her to this point, though, is close to unimaginable. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. How can gene variants affect health and development? The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). (2014) 15:16. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 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). Cereb Circ Cogn Behav. Zagaglia Selch C, Nisevic JR, et al. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. doi: 10.1001/archophthalmol.2010.42, 10. 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. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). NORD is a registered 501(c)(3) charity organization. my mom suggested we call Boston Childrens Hospital. The first time he came to meet us, Zeeva threw a sock at him. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. doi: 10.1111/j.1469-8749.2011.04198.x, 26. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Genet Med. COL4A1 is an essential component for basal membrane stability. In addition to porencephaly there can be other forms of damage to the brain present at birth. Danbury, CT 06810 Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 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. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. 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). In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Clinical Testing and Workup Phone: 202-588-5700. Progressive cerebral atrophies in three children with COL4A1 mutations. She also showed severe hypermetropia. National Center for Biotechnology Information. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Unauthorized use of these marks is strictly prohibited. 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. (2015) 17:40524. Facebook: https://www.facebook.com/Col4A1Foundation Please Note small vessel disease: a systematic review. Teaching families how to advocate for their loved ones and access medical information. This page is currently unavailable. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Eur J Med Genet. IV-3 goes to a normal school, but special schooling is required for IV-6. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. These exceptions are nuanced and should be discussed with a genetic counselor. I cannot describe the feeling of seeing your child healed. Disease Overview. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Years published: 2019. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. 4 Both . (2004) 62:16135. Phone: 203-263-9938 All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 2011 30. National Institute of Neurological Disorders and Stroke. Epub 2016 Apr 24. doi: 10.1056/NEJMoa053727, 7. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. The surgery With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Would you like email updates of new search results? Phone: 202-588-5700. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 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. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role and transmitted securely. Cavalin M, Mine M, Philbert M, et al. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. (2010) 75:7479. Curr Opin Neurol. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. Neurology. Hereditary cerebral small vessel diseases: a review. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. To use the sharing features on this page, please enable JavaScript. FOIA An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. doi: 10.1212/WNL.0000000000001309, 8. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Maybe try a search? The COL4A2 test was negative. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Phone: 617-249-7300, Danbury, CT office 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. Bookshelf Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. In the brain, intracerebral hemorrhage is the most frequent phenotype. N Engl J Med. An official website of the United States government. If either parent also carries the mutation, it is considered inherited. The number of genes implicated in epilepsy has grown rapidly in the past decade. Prenatal clinical manifestations in individuals with COL4A1/2 variants. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Individuals with HANAC syndrome also experience a variety of eye problems. In the brain, intracerebral hemorrhage is the most frequent phenotype. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. J Neurol Sci. Genet Med. Contact a health care provider if you have questions about your health. When these ropes are secreted, they assemble into net-like structures outside the cells. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . doi: 10.1111/cge.12543. 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%). Ann Bethesda, MD 20894, Web Policies Autosomal Dominant Familial Porencephaly Type I. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Am J Neuroradiol. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 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). GeneReviews. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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. doi: 10.1212/WNL.0000000000000837, 20. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. doi: 10.1111/cge.12379, 13. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. 8600 Rockville Pike In cases where the mutation is inherited, the carrier parent is often clinically unaffected. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
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