Gould Syndrome is an ultra rare genetic, multi-system disorder. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 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. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. eCollection 2022. COL4A1 and COL4A2 are on Chr. Bone. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Doctors and researchers to bring research and medical therapeutic options to those affected. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 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. 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. Washington, DC 20036 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. cutting tissue called the corpus callosum, then make some additional delicate In the human genome, there are 46 chromosomes. 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. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Ann 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Clin Neurol Neurosurg. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. doi: 10.1038/jp.2013.135, 29. Childhood presentation of COL4A1 mutations. TTY: (866) 411-1010 Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. (2015) 88:46873. 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. Gould Syndrome is an ultra rare genetic, multi-system disorder. No microbleeds or cystic cavities were found. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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). Genet Med. Fax: 203-263-9938, Washington, DC Office He smiled, caught it, and asked Zeeva if he could throw it back. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Accessibility J Med Genet. To use the sharing features on this page, please enable JavaScript. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. J Neurol Sci. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. IV-3 goes to a normal school, but special schooling is required for IV-6. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Figure 3. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. (2012) 54:56974. How are genetic conditions treated or managed? Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. (No doctor had ever taken a call on their lunch break to speak with me). Stroke is a leading cause of death and serious long-term disability in developed nations. 128:4839. 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). He was confident this would reduce or stop the This page is currently unavailable. 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. (2002) 112:198202. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. official website and that any information you provide is encrypted Cereb Circ Cogn Behav. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. How are genetic conditions treated or managed? Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. In people with HANAC syndrome, angiopathy affects several parts of the body. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. PS: wrote thi paper and performed the review of the literature under the supervision of GN. (1982) 40:5679. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Matrix Biol. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2011 The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. In the brain, intracerebral hemorrhage is the most frequent phenotype. 2010 Aug;41(8):e513-8. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. percent confident in Dr. Madsen and the epilepsy team. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. The severity of the condition varies greatly among affected individuals. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. MedlinePlus also links to health information from non-government Web sites. (18) and Staals et al. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. 2010 Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. 30. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES At least 50 individuals with this condition have been described in the scientific literature. Graefe's Arch Clin Exp Ophthalmol. (2005) 308:116771. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). We believe that the variant p.Gly743Val is likely pathogenic for several reasons. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Before For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 The first time he came to meet us, Zeeva threw a sock at him. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. 2010;17(13):1317-24. doi: Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. (2004) 62:16135. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Nearly half of these participants were diagnosed with infantile spasms. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. BMC Med Genet. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. Autosomal Dominant Familial Porencephaly Type I. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. National Institute of Neurological Disorders and Stroke. What does it mean if a disorder seems to run in my family? Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. doi: 10.1056/NEJMoa071906, 14. Childhood presentation of COL4A1 mutations. This is called genotype-phenotype correlation. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Mutations in the COL4A1 gene cause HANAC syndrome. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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/. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Neurology. COL4A1 mutations as a monogenic cause of cerebral Phone: 202-588-5700. It is important to discuss these concepts with a genetic counselor and understand their implications. 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. Standardized (15) familiar pedigree is showed in Figure 1. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. (2015) 84:91826. (1987) 8:4216. 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. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Neurology. Eur J Med Genet. doi: 10.1007/s00417-014-2800-6, 12. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Am J Neuroradiol. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). doi: 10.1126/science.1109418, 5. The COL4A1 and COL4A2 genes were screened in proband IV-6. my mom suggested we call Boston Childrens Hospital. It affects mainly young adults, children and more typically neonates. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Seattle, WA: University of Washington, Seattle; 1993-. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. doi: 10.1111/cge.12543. No use, distribution or reproduction is permitted which does not comply with these terms. Please note that NORD provides this information for the benefit of the rare disease community. Various muscles can be affected and muscle strength can become weakened. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Quincy, MA 02169 The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 2009 Jun 25 [updated 2016 Jul 7]. (2014) 83:122834. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Axenfeld-Rieger anomaly and cataract can cause impaired vision. 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. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Autosomal Dominant Brain Small Vessel Disease. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. (2006) 43:4905. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. (2009) 73:187382. If we dont have a program for you now, please continue to check back with us. 2012;21:R97-R110. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. 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. 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. Internet. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently.