Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Lanfranconi S, Markus HS. 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. In addition to porencephaly there can be other forms of damage to the brain present at birth. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: Mutations in the COL4A1 gene cause HANAC syndrome. 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. Phone: 203-263-9938 COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. It is passed through families in a autosomal dominant fashion. In the human genome, there are 46 chromosomes. Your support helps to ensure everyones free access to NORDs rare disease reports. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. People listened to us and to Zeeva in a very different and proactive way. Curr Med Chem. 1A-B). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. Neuropediatrics. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. TTY: (866) 411-1010 seizure activity. I cannot describe the feeling of seeing your child healed. small vessel disease: a systematic review. Progressive cerebral atrophies in three children with COL4A1 mutations. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Science. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Treatment COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Childhood presentation of COL4A1 mutations. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Internet. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). MeSH She also showed severe hypermetropia. If we dont have a program for you now, please continue to check back with us. Please note that NORD provides this information for the benefit of the rare disease community. 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. Neurology. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 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). She has regular physical, speech, and occupational therapy. Please note that NORD provides this information for the benefit of the rare disease community. Phone: 617-249-7300, Danbury, CT office Resource(s) for Medical Professionals and Scientists on This Disease: Stroke is a leading cause of death and serious long-term disability in developed nations. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. eCollection 2022. 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. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. NCI CPTC Antibody Characterization Program. Before To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . II-2 had a limp since childhood attributed to forceps delivery. Recent findings: Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. 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 . N Engl J Med. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Early intervention is important in ensuring that children with reach their highest potential. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. NORD strives to open new assistance programs as funding allows. Stroke. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. The severity of the condition varies greatly among affected individuals. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. How can gene variants affect health and development? ClinVar; [VCV000389182.3]. MedlinePlus also links to health information from non-government Web sites. The signs and symptoms can manifest at almost any age from before birth to old age. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Jeanne M, Gould DB. (2017) 377:111931. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). It looks like nothing was found at this location. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). The .gov means its official. Standardized (15) familiar pedigree is showed in Figure 1. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. 8600 Rockville Pike More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. (2008) 17:42433. No use, distribution or reproduction is permitted which does not comply with these terms. National Center for Biotechnology Information. In the brain, intracerebral hemorrhage is the most frequent phenotype. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. (19). Eur J Paediatr Neurol. functional hemispherectomy. (2014) 11:3612. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. INTERNET In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Suite 500 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). Arch Ophthalmol. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. What does it mean if a disorder seems to run in my family? Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Maybe try a search? 2011 Surgery may be necessary for individuals with severe cataracts. Graefe's Arch Clin Exp Ophthalmol. doi: 10.1212/01.WNL.0000123113.46672.68, 25. (1982) 40:5679. At least 50 individuals with this condition have been described in the scientific literature. (2018) 91:e207888. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. When we didnt feel we had any options left for treatment, Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. doi: 10.1056/NEJMoa053727, 7. NORD is a registered 501(c)(3) charity organization. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 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. 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). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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. This group rarely survives beyond 2 years. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. This condition causes mutations in genes that produce a specific type of collagen. FOIA Childhood presentation of COL4A1 mutations. Neurol. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Genet Med. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. doi: 10.1212/WNL.0b013e3181c3fd12, 9. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Most individuals diagnosed with a COL4A1-related disorder have an affected parent. If either parent also carries the mutation, it is considered inherited. Suite 310 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. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. doi: 10.1212/WNL.0000000000000837, 20. Years published: 2019. Congenital Cephalic Disorders Summary: Ann Neurol. 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 1. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Cereb Circ Cogn Behav. doi: 10.1007/s10897-008-9169-9, 16. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (2015) 17:84353. 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. Bennett RL, French KS, Resta RG, Doyle DL. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. He would separate the two halves of her brain by COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. (2015) 88:46873. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Please enable it to take advantage of the complete set of features! (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The information on this site should not be used as a substitute for professional medical care or advice. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Cephalic Disorders Fact Sheet. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Seattle, WA: University of Washington, Seattle; 1993-. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. 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. 4 Both . (2004) 62:16135. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Teaching families how to advocate for their loved ones and access medical information. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 11:827. doi: 10.3389/fneur.2020.00827. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. doi: 10.1111/cge.12543. It is not uncommon for an unaffected parent to have a severely affected child. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. It is ubiquitously expressed in many tissues and cell types. 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. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Stroke. J Neurol Sci. official website and that any information you provide is encrypted The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Thats not to say Zeeva hasnt had to work hard since the surgery. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. In most people, small vessel disease in the brain does not cause symptoms. 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. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: The disorder causes many symptoms, not the least of which are strokes and epilepsy. His bedside manner was incredible. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. COL4A1 mutations as a monogenic cause of cerebral 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. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Dev Med Child Neurol. doi: 10.1126/science.1109418, 5. 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. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 1779 Massachusetts Avenue IV-3 was diagnosed with ventriculomegaly in utero. 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. (2015) 84:91826. Figure 3. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Understanding what it has taken to get her to this point, though, is close to unimaginable. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. (2010) 14:1827. 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Ophthalmological features associated with COL4A1 mutations. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. (2009) 73:187382. Type IV collagen molecules attach to each other to form complex protein networks.

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