Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Suite 500 The COL4A2 test was negative. Quincy, MA 02169 Genet Med. Washington, DC 20036 Suite 310 The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. INTERNET Curr Opin Neurol. government site. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Resource(s) for Medical Professionals and Scientists on This Disease: National Institute of Neurological Disorders and Stroke. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Neurology. We provide education, advocacy, and resources for families and individuals affected. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. small vessel disease: a systematic review. 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. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Gould Syndrome is a rare, genetic, multi-system disorder. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. (2015) 84:91826. A diagnosis can be confirmed through molecular genetic testing. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 10.1161/STROKEAHA.110.581918. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. 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). In the human genome, there are 46 chromosomes. https://www.ncbi.nlm.nih.gov/pubmed/26610912. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. COL4A1 mutations as a monogenic cause of cerebral (2006) 354:148996. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. (2009) 73:187382. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. Curr Med Chem. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Berg R, Aleck A, Kaplan A. Familial porencephaly. Dr. Madsen suggested Zeeva have an operation called a 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. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. No use, distribution or reproduction is permitted which does not comply with these terms. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. The risk is the same for males and females. Curr Opin Neurol. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Disclaimer. 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: (2015) 17:84353. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. J Neurol Sci. (2017) 5758:2944. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. 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. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. doi: 10.1126/science.1109418, 5. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 55 Kenosia Avenue More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. doi: 10.1001/archneur.1983.04050080067013, 17. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. (2010). Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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). How can gene variants affect health and development? Six alpha chains of type IV. Nearly half of these participants were diagnosed with infantile spasms. 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). Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. This condition causes mutations in genes that produce a specific type of collagen. BMC Med Genet. Please note that NORD provides this information for the benefit of the rare disease community. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) Type IV collagen molecules attach to each other to form complex protein networks. 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. 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. IV-3 goes to a normal school, but special schooling is required for IV-6. In the human genome, there are 46 chromosomes. Painful muscle cramps can occur and can develop before three years of age. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. The first time he came to meet us, Zeeva threw a sock at him. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. 30. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 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. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Dev Med Child Neurol. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. official website and that any information you provide is encrypted The information on this site should not be used as a substitute for professional medical care or advice. September 2003. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. At least 50 individuals with this condition have been described in the scientific literature. (2008) 23:17. Disease Overview. Some individuals develop cysts on the kidney. 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. Summary. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. He was confident this would reduce or stop the Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. While there are other explanations, parental mosaicism should be considered. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Purpose of review: (1982) 40:5679. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. PS: wrote thi paper and performed the review of the literature under the supervision of GN. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 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. Please note that NORD provides this information for the benefit of the rare disease community. No microbleeds or cystic cavities were found. J Med Genet. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. However, there are exceptions that depend on precisely when and where the mutation arose. doi: 10.1136/jmg.2005.035584, 15. 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. Acute urinary retention due to a novel collagen COL4A1 mutation. 2011 He would separate the two halves of her brain by doi: 10.1002/ana.23736, 4. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. doi: Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Stroke. 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. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 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. 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). When we didnt feel we had any options left for treatment, N Engl J Med. 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 latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Science. Arch Neurol. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 2009 Jun 25 [updated 2016 Jul 7]. 1779 Massachusetts Avenue The number of genes implicated in epilepsy has grown rapidly in the past decade. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. (2005) 308:116771. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 1900 Crown Colony Drive The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. (2010) 75:7479. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Individuals with HANAC syndrome also experience a variety of eye problems. . Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. PMC Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. 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. 128:4839. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region.