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MedlinePlus also links to health information from non-government Web sites. Pediatr Neurol. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. The surgery Washington, DC 20036 For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Stroke. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Jeanne M, Gould DB. 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. doi: 10.1056/NEJMoa1707914, 6. 2018;61:765-772. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). 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. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. and transmitted securely. Danbury, CT 06810 eCollection 2022. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 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 . Written informed consent was obtained from the patient and the patient's parents for publication of this case report. 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). It is passed through families in a autosomal dominant fashion. 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. How are genetic conditions treated or managed? Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. Autosomal Dominant Brain Small Vessel Disease. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Neurology. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. (19). Neurology. This condition causes mutations in genes that produce a specific type of collagen. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. doi: 10.1016/j.ejpn.2009.04.010, 27. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Changing lives of those with rare disease. Facebook: https://www.facebook.com/Col4A1Foundation Please Note (2005) 308:116771. doi: 10.1001/archophthalmol.2010.42, 10. 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 first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. This page is currently unavailable. doi: 10.1007/s00417-014-2800-6, 12. It is ubiquitously expressed in many tissues and cell types. COL4A1 mutations as a monogenic cause of cerebral Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Dr. Madsen suggested Zeeva have an operation called a 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. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. seizure activity. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. PMC When we didnt feel we had any options left for treatment, What does it mean if a disorder seems to run in my family? (2002) 112:198202. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. (2008) 23:17. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Nat Methods. If we dont have a program for you now, please continue to check back with us. ACS Omega. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Firstly, it segregates within the family with the phenotype. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Neurology. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. 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. It affects mainly young adults, children and more typically neonates. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 4 Both . came with risks and was the hardest decision we had ever faced, yet we felt 100 Genet Med. He was confident this would reduce or stop the Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. (2010) 14:1827. We provide education, advocacy, and resources for families and individuals affected. Neurologic phenotypes associated with COL4A1/2 mutations However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 2011 Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. doi: 10.1007/s10897-008-9169-9, 16. Collagen, type IV, alpha 1 - Wikipedia Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. J Neurol Sci. for the triple helical CB3[IV] domain. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. N Engl J Med. Various muscles can be affected and muscle strength can become weakened. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Gould Syndrome is an ultra rare genetic, multi-system disorder. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. IV-3 was diagnosed with ventriculomegaly in utero. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Copyright 2023 by Gould Syndrome Foundation -. What does it mean if a disorder seems to run in my family? Bone. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. 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. 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 expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Clin Neurol Neurosurg. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role National Institute of Neurological Disorders and Stroke. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. How can gene variants affect health and development? 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. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Clinical Testing and Workup 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. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Ann Neurol. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Danbury, CT 06810 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. He smiled, caught it, and asked Zeeva if he could throw it back. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. National Library of Medicine Clin Genet. 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. Am J Med Genet A. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Neurol. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). 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. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. COL4A1 brain small-vessel disease - Radiopaedia Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. doi: 10.1212/WNL.0000000000000837, 20. 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. Disease Overview. (2012) 54:56974. HANAC syndrome is a rare condition, although the exact prevalence is unknown. doi: 10.1056/NEJMoa071906, 14. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible.