Matrix Biol. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Maybe try a search? Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. small vessel disease: a systematic review. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Your support helps to ensure everyones free access to NORDs rare disease reports. Summary. September 2003. N Engl J Med. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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). (2012) 54:56974. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. COL4A1 Syndrome CADASIL Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. and transmitted securely. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Type IV collagen molecules attach to each other to form complex protein networks. Prenatal clinical manifestations in individuals with COL4A1/2 variants. doi: 10.1186/s12881-014-0097-2, 11. Neurology. my mom suggested we call Boston Childrens Hospital. sharing sensitive information, make sure youre on a federal 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). Please enable it to take advantage of the complete set of features! 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. Neurology. 30. The COL4A2 test was negative. Bookshelf The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Bennett RL, French KS, Resta RG, Doyle DL. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. It is passed through families in a autosomal dominant fashion. In addition to porencephaly there can be other forms of damage to the brain present at birth. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Muscle cramps can be spontaneous or triggered by exercise. 1779 Massachusetts Avenue (2010) 75:7479. However, there are exceptions that depend on precisely when and where the mutation arose. Early intervention is important in ensuring that children with reach their highest potential. 1. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 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. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. COL4A1 is an essential component for basal membrane stability. 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). If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. What are the different ways a genetic condition can be inherited? Antiinflammatory therapy with canakinumab for atherosclerotic disease. 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). Still other individuals may not develop any symptoms until well into adulthood. Jeanne M, Gould DB. Zeevas brain to treat a cyst in her brain caused by porencephaly. HANAC syndrome is caused by genetic changes in the COL4A1 gene. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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. 1900 Crown Colony Drive doi: 10.1007/s00417-014-2800-6, 12. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. 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 . Collagen, type IV, alpha 1 - Wikipedia Quincy, MA 02169 Nearly half of these participants were diagnosed with infantile spasms. The severity of the condition varies greatly among affected individuals. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Ultrasound in utero from IV-6 (A). In the human genome, there are 46 chromosomes. NORD is a registered 501(c)(3) charity organization. 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. 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 https:// ensures that you are connecting to the (2015) 84:91826. Stroke is a leading cause of death and serious long-term disability in developed nations. Bone. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Purpose of review: The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. 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. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel Bull Acad Natl Med. Epilepsy and related challenges in children with COL4A1 and - PubMed Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2017) 377:111931. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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. (2011) 42:13. He also wanted to remove a shunt that was implanted in As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. IV-3 goes to a normal school, but special schooling is required for IV-6. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Standardized (15) familiar pedigree is showed in Figure 1. came with risks and was the hardest decision we had ever faced, yet we felt 100 What is Gould Syndrome? - Gould Syndrome Foundation This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. COL4A1 mutations as a monogenic cause of cerebral Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Fetal intracerebral hemorrhage and cataract: think COL4A1. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 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. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Neurologic phenotypes associated with COL4A1/2 mutations The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 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. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 2018;61:765-772. Agenesis of the Corpus Callosum | National Institute of Neurological COL4A1 -Related Disorders - PubMed The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. The surgery Neurology. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. doi: 10.1212/WNL.0000000000000837, 20. functional hemispherectomy. Six alpha chains of type IV. COL4A1 mutations in patients with sporadic late-onset intracerebral PMC Resource(s) for Medical Professionals and Scientists on This Disease: The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 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. How are genetic conditions treated or managed? Phone: 617-249-7300, Danbury, CT office Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. (2006) 43:4905. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Neurology. 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. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. (2008) 17:42433. If we dont have a program for you now, please continue to check back with us. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Pediatr Neurol. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 4 Both . Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 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Autosomal Dominant Familial Porencephaly Type I. The first time he came to meet us, Zeeva threw a sock at him. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. 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). 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: Plaisier E, Ronco P. COL4A1-Related Disorders. doi: 10.1212/WNL.0000000000001309, 8. How can gene variants affect health and development? Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Genet Med. 10.1161/STROKEAHA.110.581918. 10.2174/092986710790936293. 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). Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Col4a1 mutation generates vascular abnormalities correlated with The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date.