col4a1 syndrome life expectancy

Resource(s) for Medical Professionals and Scientists on This Disease: This group rarely survives beyond 2 years. At least 50 individuals with this condition have been described in the scientific literature. 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 . All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. All authors contributed to the article and approved the submitted version. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. What are the different ways a genetic condition can be inherited? National Institute of Neurological Disorders and Stroke. N Engl J Med. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Bookshelf 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. 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). Ophthalmological features associated with COL4A1 mutations. TTY: (866) 411-1010 Changing lives of those with rare disease. 2011 In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. This condition causes mutations in genes that produce a specific type of collagen. What is the prognosis of a genetic condition? (2014) 252:178994. BMC Med Genet. J Neurol Sci. There are no standardized treatment protocols or guidelines for affected individuals. (2015) 88:46873. It is passed through families in a autosomal dominant fashion. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. NORD is a registered 501(c)(3) charity organization. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Jeanne M, Gould DB. 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.) COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 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). Figure 3. Neurology. 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. COL4A1 is an essential component for basal membrane stability. 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. Graefe's Arch Clin Exp Ophthalmol. 10.2174/092986710790936293. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. J Genet Couns. doi: 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). COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 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. Treatment Careers. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. How are genetic conditions treated or managed? 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Surgery may be necessary for individuals with severe cataracts. 128:4839. for the triple helical CB3[IV] domain. PMC Seattle, WA: University of Washington, Seattle; 1993-. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. (2014) 15:16. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. doi: 10.1212/WNL.0000000000001309, 8. 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 first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. (2017) 377:111931. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). 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). 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. 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. HHS Vulnerability Disclosure, Help Before In the human genome, there are 46 chromosomes. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Ann Neurol. 1779 Massachusetts Avenue COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. In people with HANAC syndrome, angiopathy affects several parts of the body. The https:// ensures that you are connecting to the She, then, developed seizures which were controlled by valproic acid. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Neurology. The site is secure. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Migraines can occur with or without aura. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. 2018;61:765-772. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). COL4A1 Syndrome CADASIL For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Contact a health care provider if you have questions about your health. Washington, DC 20036 In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Nat Methods. (2015) 17:40524. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Cephalic Disorders Fact Sheet. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. IV-3 goes to a normal school, but special schooling is required for IV-6. We provide education, advocacy, and resources for families and individuals affected. (2004) 62:16135. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Prenatal clinical manifestations in individuals with COL4A1/2 variants. The COL4A1 stroke syndrome. If either parent also carries the mutation, it is considered inherited. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. What does it mean if a disorder seems to run in my family? Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. The COL4A2 test was negative. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. 2010;17(13):1317-24. doi: 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Dev Med Child Neurol. NCI CPTC Antibody Characterization Program. Last updated: Curr Opin Neurol. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Gould Syndrome is a rare, genetic, multi-system disorder. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Pediatr Neurol. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 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. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The size and location of cerebral cavities contributes to clinical variability. MeSH 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. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). doi: 10.1001/archophthalmol.2010.42, 10. January 31, 2019 In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Therapies are based on the specific symptoms in each individual. Years published: 2019. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Still other individuals may not develop any symptoms until well into adulthood. COL4A1 mutations as a monogenic cause of cerebral PV and VW followed the children at the Neuropediatrics clinic of the same hospital. doi: 10.1055/s-0031-1275343, 24. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. (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). Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 30. (2015) 17:84353. Quincy, MA 02169 (2017) 5758:2944. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. In most people, small vessel disease in the brain does not cause symptoms. He would separate the two halves of her brain by 2010 Suite 310 While there are other explanations, parental mosaicism should be considered. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. What is the prognosis of a genetic condition? To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 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. Changing lives of those with rare disease. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. (2020). Neurology. Pathology. 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/. Fax: 203-263-9938, Washington, DC Office Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Contact a health care provider if you have questions about your health. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Danbury, CT 06810 Painful muscle cramps can occur and can develop before three years of age. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. COL4A1/A2-related disorders are dominant genetic disorders.

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