Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. (2015) 84:91826. 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 . 2008 May;192(5):971-84; discussion 984-6. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. (2006) 354:148996. 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. can also contribute. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Progressive cerebral atrophies in three children with COL4A1 mutations. Science. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Seattle, WA: University of Washington, Seattle; 1993-. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). (2014) 11:3612. Neurology. It is not uncommon for an unaffected parent to have a severely affected child. One patient (IV-3) was treated for spasticity and seizures with valproic acid. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. 1779 Massachusetts Avenue J Genet Couns. Epub 2016 Apr 24. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. 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. Ann Neurol. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. It is important to discuss these concepts with a genetic counselor and understand their implications. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. We provide education, advocacy, and resources for families and individuals affected. 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. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Arch Ophthalmol. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. 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. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 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. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. Jeanne M, Gould DB. Washington, DC 20036 Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Bookshelf seizure activity. 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). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. In most cases, an affected person has one parent with the condition. Neurology. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. However, in people with HANAC syndrome, these aneurysms typically do not burst. The information on this site should not be used as a substitute for professional medical care or advice. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. 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). Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Fax: 203-263-9938, Washington, DC Office COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. TTY: (866) 411-1010 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. eCollection 2021. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Summary. In the human genome, there are 46 chromosomes. Phone: 617-249-7300, Danbury, CT office Therapies are based on the specific symptoms in each individual. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The severity of the condition varies greatly among affected individuals. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: eCollection 2022. It looks like nothing was found at this location. 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. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 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. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Neurology. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Thats not to say Zeeva hasnt had to work hard since the surgery. At least 50 individuals with this condition have been described in the scientific literature. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 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. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 2009 Jun 25 [updated 2016 Jul 7]. (2020). Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. The site is secure. It affects mainly young adults, children and more typically neonates. Quincy, MA 02169 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/. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. (1987) 8:4216. 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. (2011) 42:13. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Suite 310 Unable to load your collection due to an error, Unable to load your delegates due to an error. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 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. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. While there are other explanations, parental mosaicism should be considered. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Danbury, CT 06810 Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. GeneReviews. Neurology. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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). 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. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. COL4A1/A2-related disorders are dominant genetic disorders. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Type IV collagen molecules attach to each other to form complex protein networks. Bull Acad Natl Med. The size and location of cerebral cavities contributes to clinical variability. Zagaglia Selch C, Nisevic JR, et al. Axenfeld-Rieger anomaly and cataract can cause impaired vision. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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.) The first time he came to meet us, Zeeva threw a sock at him. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Am J Med Genet A. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. (2018) 91:e207888. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Accessibility Recent findings: Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Neurol. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Internet. Some individuals develop cysts on the kidney. Clinical Testing and Workup HANAC syndrome is caused by genetic changes in the COL4A1 gene. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. All authors contributed to the article and approved the submitted version. 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. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Clin Genet. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. doi: 10.1001/archophthalmol.2010.42, 10. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Cereb Circ Cogn Behav. doi: 10.1186/s12881-014-0097-2, 11. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. The .gov means its official. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. J Med Genet. He would separate the two halves of her brain by COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. (2008) 23:17. The https:// ensures that you are connecting to the MeSH U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. 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. INTERNET Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Neurol. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. doi: In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. doi: 10.1056/NEJMoa071906, 14. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Genet Med. (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). MedlinePlus also links to health information from non-government Web sites. Prenatal clinical manifestations in individuals with COL4A1/2 variants. 1900 Crown Colony Drive IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 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%). 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. government site. Dev Med Child Neurol. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Figure 3. Cephalic Disorders Fact Sheet. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020).