What are the different ways a genetic condition can be inherited? Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Years published: 2019. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Practical approach to the diagnosis of adult-onset - BMJ Lenses corrected for hypermetropia. The https:// ensures that you are connecting to the Neurology. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. doi: 10.1212/WNL.0000000000001309, 8. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Internet. PS: wrote thi paper and performed the review of the literature under the supervision of GN. COL4A1 brain small-vessel disease - Radiopaedia The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Epub 2014 Jan 5. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 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 reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke doi: 10.1016/j.ejpn.2009.04.010, 27. doi: 10.1007/s10897-008-9169-9, 16. He would separate the two halves of her brain by Would you like email updates of new search results? 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. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. ACS Omega. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. 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. Six alpha chains of type IV. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 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. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). (2020). Zagaglia Selch C, Nisevic JR, et al. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Neurology. Clinical Testing and Workup Washington, DC 20036 11:827. doi: 10.3389/fneur.2020.00827. 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. (2015) 17:40524. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). If we dont have a program for you now, please continue to check back with us. Dev Med Child Neurol. Phone: 203-263-9938 for the triple helical CB3[IV] domain. ClinVar; [VCV000389182.3]. 55 Kenosia Avenue She also showed severe hypermetropia. Neurology. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Axenfeld-Rieger anomaly and cataract can cause impaired vision. . 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. When these ropes are secreted, they assemble into net-like structures outside the cells. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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, . To use the sharing features on this page, please enable JavaScript. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 10.1161/STROKEAHA.110.581918. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Before The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Early intervention is important in ensuring that children with reach their highest potential. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 People listened to us and to Zeeva in a very different and proactive way. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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). Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. She has regular physical, speech, and occupational therapy. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The surgery At least six affected families have been described in the scientific literature. (2012) 54:56974. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Stroke. (2002) 112:198202. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Berg R, Aleck A, Kaplan A. Familial porencephaly. 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. doi: 10.1001/archophthalmol.2010.42, 10. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Affected individuals may have no observable symptoms or only isolated migraines with aura. In people with HANAC syndrome, angiopathy affects several parts of the body. Science. 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. Nearly half of these participants were diagnosed with infantile spasms. Clipboard, Search History, and several other advanced features are temporarily unavailable. Further refinement of COL4A1 and COL4A2 related cortical malformations. Resource(s) for Medical Professionals and Scientists on This Disease: The severity of the condition varies greatly among affected individuals. Clin Neurol Neurosurg. How can gene variants affect health and development? While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. 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. Last updated: 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. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Changing lives of those with rare disease. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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). National Institute of Neurological Disorders and Stroke. (2011) 42:13. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 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. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. These exceptions are nuanced and should be discussed with a genetic counselor. 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. Acute urinary retention due to a novel collagen COL4A1 mutation. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 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. doi: 10.1111/cge.12379, 13. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. J Perinatol. We provide education, advocacy, and resources for families and individuals affected. Neurology. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. However, in people with HANAC syndrome, these aneurysms typically do not burst. In addition to porencephaly there can be other forms of damage to the brain present at birth. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Epub 2016 Apr 24. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. January 31, 2019 Neurology. Purpose of review: It is passed through families in a autosomal dominant fashion. FOIA MedlinePlus also links to health information from non-government Web sites. seizure activity. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 COL4A1 mutations as a monogenic cause of cerebral Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Progressive cerebral atrophies in three children with COL4A1 mutations. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Treatment Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The number of genes implicated in epilepsy has grown rapidly in the past decade. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. doi: 10.1038/gim.2015.30, 21. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Neurologic phenotypes associated with COL4A1/2 mutations It is not uncommon for an unaffected parent to have a severely affected child. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. 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. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Antiinflammatory therapy with canakinumab for atherosclerotic disease. 2010;17(13):1317-24. doi: COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. 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 conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Autosomal Dominant Brain Small Vessel Disease. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. MeSH Accessibility One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 30. 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. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Gould Syndrome is an ultra rare genetic, multi-system disorder. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. If either parent also carries the mutation, it is considered inherited. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Disclaimer. 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Dev Med Child Neurol. doi: 10.1038/gim.2014.210, 3. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Surgery may be necessary for individuals with severe cataracts. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). (2014) 83:122834. 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