55 Kenosia Avenue Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). HHS Vulnerability Disclosure, Help I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. The surgery 2011 Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Treatment 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. 2011 NORD is a registered 501(c)(3) charity organization. Before Ann Neurol. doi: Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Internet. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Suite 310 Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). J Genet Couns. How can gene variants affect health and development? What are the different ways a genetic condition can be inherited? Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. doi: 10.1016/j.ejpn.2009.04.010, 27. Changing lives of those with rare disease. Nat Methods. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Maybe try a search? 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. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Genet Med. COL4A1/A2-related disorders are dominant genetic disorders. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Jeanne M, Gould DB. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Jeanne M, Gould DB. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Neurology. 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 mutations cause progressive retinal neovascular defects and retinopathy. Mutations in the COL4A1 gene cause HANAC syndrome. 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 extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. COL4A1 mutations as a monogenic cause of cerebral Muscle cramps can be spontaneous or triggered by exercise. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). 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. Please note that NORD provides this information for the benefit of the rare disease community. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. 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 expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 1. COL4A1 is an essential component for basal membrane stability. No microbleeds or cystic cavities were found. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. TTY: (866) 411-1010 Disclaimer. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. The number of genes implicated in epilepsy has grown rapidly in the past decade. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Teaching families how to advocate for their loved ones and access medical information. What does it mean if a disorder seems to run in my family? mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. ClinVar; [VCV000389182.3]. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 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. In the human genome, there are 46 chromosomes. Standardized (15) familiar pedigree is showed in Figure 1. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Careers. Suite 500 official website and that any information you provide is encrypted Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (No doctor had ever taken a call on their lunch break to speak with me). He also wanted to remove a shunt that was implanted in Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: When we didnt feel we had any options left for treatment, GeneReviews. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: The first time he came to meet us, Zeeva threw a sock at him. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, 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. (2008) 23:17. Firstly, it segregates within the family with the phenotype. Years published: 2019. When this enzyme is elevated, it is a sign of muscle damage. sharing sensitive information, make sure youre on a federal She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. (2009) 73:187382. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. 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.) Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. NORD strives to open new assistance programs as funding allows. Arch Neurol. N Engl J Med. The severity of the condition varies greatly among affected individuals. 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). Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. We provide education, advocacy, and resources for families and individuals affected. doi: 10.1186/s12881-014-0097-2, 11. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 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. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. 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 type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Facebook: https://www.facebook.com/Col4A1Foundation Please Note At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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. 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).