col4a1 syndrome life expectancy

COL4A1/A2-related disorders are rare, genetic, multi-system disorders. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Years published: 2019. doi: 10.1007/s00417-014-2800-6, 12. Jeanne M, Gould DB. Eur J Med Genet. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. 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). J Perinatol. The disorder causes many symptoms, not the least of which are strokes and epilepsy. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke (2004) 62:16135. 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, . Epub 2016 Apr 24. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. However, in people with HANAC syndrome, these aneurysms typically do not burst. HHS Vulnerability Disclosure, Help COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. ACS Omega. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. She, then, developed seizures which were controlled by valproic acid. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 10.1161/STROKEAHA.110.581918. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Dr. Madsen suggested Zeeva have an operation called a eCollection 2022 Nov 8. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. doi: 10.1016/j.ejpn.2009.04.010, 27. Surgery may be necessary for individuals with severe cataracts. official website and that any information you provide is encrypted Clin Neurol Neurosurg. 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). Dev Med Child Neurol. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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). eCollection 2022. (2014) 11:3612. Type IV collagen molecules attach to each other to form complex protein networks. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. No microbleeds or cystic cavities were found. People with COL4A1-related brain small vessel disease also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. doi: 10.1038/gim.2014.210, 3. Some individuals develop cysts on the kidney. doi: 10.1111/cge.12379, 13. 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). The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. 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. Childhood presentation of COL4A1 mutations. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. 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/. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). NCI CPTC Antibody Characterization Program. 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. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. (2015) 17:84353. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome 11:827. doi: 10.3389/fneur.2020.00827. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. In the brain, intracerebral hemorrhage is the most frequent phenotype. Genet Med. (19). (2018) 91:e207888. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. An official website of the United States government. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Cavalin M, Mine M, Philbert M, et al. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Unable to load your collection due to an error, Unable to load your delegates due to an error. In most people, small vessel disease in the brain does not cause symptoms. The surgery Matrix Biol. 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. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Cereb Circ Cogn Behav. It is not uncommon for an unaffected parent to have a severely affected child. 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. Epilepsy and related challenges in children with COL4A1 and - PubMed Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. The COL4A1 stroke syndrome. 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. 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.) (2002) 112:198202. The COL4A1 and COL4A2 genes were screened in proband IV-6. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. 55 Kenosia Avenue *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Your support helps to ensure everyones free access to NORDs rare disease reports. Am J Med Genet. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. COL4A1 Syndrome CADASIL Individuals with HANAC syndrome also experience a variety of eye problems. Nat Methods. 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. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. doi: 10.1136/jmg.2005.035584, 15. 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. Neurol. These genes are the blueprints for two proteins that wind together like a long rope inside cells. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. doi: 10.1056/NEJMoa1707914, 6. He also wanted to remove a shunt that was implanted in One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. 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). Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. It is passed through families in a autosomal dominant fashion. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Migraines can occur with or without aura. Muscle cramps can be spontaneous or triggered by exercise. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). doi: 10.1212/WNL.0000000000000837, 20. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Curr Med Chem. PMC COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. N Engl J Med. 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. 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. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. What are the different ways a genetic condition can be inherited? III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Therapies are based on the specific symptoms in each individual. 2011 The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. 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. Lanfranconi S, Markus HS. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. came with risks and was the hardest decision we had ever faced, yet we felt 100 Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Early intervention is important in ensuring that children with reach their highest potential. People listened to us and to Zeeva in a very different and proactive way. (No doctor had ever taken a call on their lunch break to speak with me). Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). doi: 10.1056/NEJMoa071906, 14. Phone: 202-588-5700. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. 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 brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Practical approach to the diagnosis of adult-onset - BMJ 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 COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. doi: 10.1111/j.1469-8749.2011.04198.x, 26. INTERNET Bone. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. This is called genotype-phenotype correlation. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. The information on this site should not be used as a substitute for professional medical care or advice. J Neurol Sci. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Eur J Paediatr Neurol. (2014) 252:178994. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Disease Overview. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 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 size and location of cerebral cavities contributes to clinical variability. Neurology. Genet Med. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Neurology. Standardized (15) familiar pedigree is showed in Figure 1. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Congenital Cephalic Disorders 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). 2010 However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 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. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). A diagnosis can be confirmed through molecular genetic testing. 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. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. I cannot describe the feeling of seeing your child healed. Neurology. What does it mean if a disorder seems to run in my family? Danbury, CT 06810 Unauthorized use of these marks is strictly prohibited. mutations: a novel genetic multisystem disease. MedlinePlus also links to health information from non-government Web sites. Careers. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). (2008) 23:17. . This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits).