The disorder causes many symptoms, not the least of which are strokes and epilepsy. my mom suggested we call Boston Childrens Hospital. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. MeSH People with HANAC syndrome develop kidney disease (nephropathy). 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. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Various muscles can be affected and muscle strength can become weakened. 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. doi: 10.1038/gim.2014.210, 3. What are the different ways a genetic condition can be inherited? Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. To use the sharing features on this page, please enable JavaScript. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Early intervention is important in ensuring that children with reach their highest potential. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the Cavalin M, Mine M, Philbert M, et al. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Epub 2016 Apr 24. Surgery may be necessary for individuals with severe cataracts. 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. Years published: 2019. Neurology. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. COL4A1/A2-related disorders are dominant genetic disorders. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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. 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. Cephalic Disorders Fact Sheet. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Science. Cereb Circ Cogn Behav. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 2018;91:e2078-e2088. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. can also contribute. Facebook: https://www.facebook.com/Col4A1Foundation Please Note A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. IV-3 was diagnosed with ventriculomegaly in utero. (2020). The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. September 2003. COL4A1 Syndrome CADASIL Still other individuals may not develop any symptoms until well into adulthood. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. functional hemispherectomy. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 30. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. (2004) 62:16135. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. How are genetic conditions treated or managed? (1982) 40:5679. (2014) 34:757. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Further refinement of COL4A1 and COL4A2 related cortical malformations. Accessibility Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. NORD is a registered 501(c)(3) charity organization. It is passed through families in a autosomal dominant fashion. INTERNET All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). 2011 Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Curr Med Chem. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. 11:827. doi: 10.3389/fneur.2020.00827. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Phone: 617-249-7300, Danbury, CT office Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. cuts under the microscope. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. The retina is the light-sensitive membrane that lines the inside of the eyes. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. The surgery Ultrasound in utero from IV-6 (A). 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). doi: 10.1186/s12881-014-0097-2, 11. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. It is important to discuss these concepts with a genetic counselor and understand their implications. (2008) 17:42433. 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. Neurol. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Teaching families how to advocate for their loved ones and access medical information. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Unable to load your collection due to an error, Unable to load your delegates due to an error. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. In the brain, intracerebral hemorrhage is the most frequent phenotype. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The site is secure. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Doctors and researchers to bring research and medical therapeutic options to those affected. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: doi: 10.1212/WNL.0000000000000837, 20. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. (2005) 308:116771. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Jeanne M, Gould DB. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. 8600 Rockville Pike Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Some individuals develop cysts on the kidney. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. All authors contributed to the article and approved the submitted version. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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. 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 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. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 2018;61:765-772. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Resource(s) for Medical Professionals and Scientists on This Disease: III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Dr. Madsen suggested Zeeva have an operation called a The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. The number of genes implicated in epilepsy has grown rapidly in the past decade. He smiled, caught it, and asked Zeeva if he could throw it back. What is the prognosis of a genetic condition? *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 4 Both . The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. Bennett RL, French KS, Resta RG, Doyle DL. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. doi: 10.1002/ana.23736, 4. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Arch Ophthalmol. Phone: 203-263-9938 COL4A1 mutations as a monogenic cause of cerebral Treatment Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. The COL4A1 and COL4A2 genes were screened in proband IV-6. Front Aging Neurosci. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. This page is currently unavailable. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). government site. 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. 10.1161/STROKEAHA.110.581918. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Dev Med Child Neurol. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Childhood presentation of COL4A1 mutations. 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. Summary: MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 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. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Genet Med. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. (2014) 11:3612. No use, distribution or reproduction is permitted which does not comply with these terms. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Hereditary cerebral small vessel diseases: a review. 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. Lanfranconi S, Markus HS. Zeevas brain to treat a cyst in her brain caused by porencephaly. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). mutations: a novel genetic multisystem disease. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. doi: 10.1111/cge.12543. 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. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Neurology. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). If either parent also carries the mutation, it is considered inherited. The COL4A1 stroke syndrome. (2018) 91:e207888. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. doi: 10.1001/archophthalmol.2010.42, 10. The severity of the condition varies greatly among affected individuals. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 2011 Front. Phone: 202-588-5700. (1987) 8:4216. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter.
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