Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. About half of people with this condition 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). Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. He also wanted to remove a shunt that was implanted in
Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). What are the different ways a genetic condition can be inherited? Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Suite 310 Autosomal Dominant Brain Small Vessel Disease. In the brain, intracerebral hemorrhage is the most frequent phenotype. 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. 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. Quincy, MA 02169 What are the different ways a genetic condition can be inherited? An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. doi: 10.1007/s10897-008-9169-9, 16. At least 50 individuals with this condition have been described in the scientific literature. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. N Engl J Med. seizure activity. Nearly half of these participants were diagnosed with infantile spasms.
What does it mean to have a COL4A1 - Little Braveheart | Facebook Orphanet: HANAC syndrome Lanfranconi S, Markus HS. 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. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 2009 Jun 25 [updated 2016 Jul 7]. 1900 Crown Colony Drive Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Am J Med Genet.
What is Gould Syndrome? - Gould Syndrome Foundation Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain.
(2017) 5758:2944. (2002) 112:198202. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. COL4A1 mutations as a monogenic cause of cerebral When these ropes are secreted, they assemble into net-like structures outside the cells. Dev Med Child Neurol. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Some individuals develop cysts on the kidney. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. 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. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. 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. (19). Ann Neurol. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Would you like email updates of new search results?
COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for 2011 In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. 30. Before 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). Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Neurology. It affects mainly young adults, children and more typically neonates. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). J Med Genet. Ann Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, The signs and symptoms can manifest at almost any age from before birth to old age. Figure 3. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. The COL4A1 stroke syndrome. 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. doi: 10.1038/nmeth.2890, 22. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. (2012) 54:56974. Clipboard, Search History, and several other advanced features are temporarily unavailable. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. . https://www.ncbi.nlm.nih.gov/pubmed/26610912. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. doi: 10.1038/gim.2014.210, 3. 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. Neurology. Stroke. When we didnt feel we had any options left for treatment, In the human genome, there are 46 chromosomes. What does it mean if a disorder seems to run in my family? Neurology. While there are other explanations, parental mosaicism should be considered. doi: 10.1056/NEJMoa1707914, 6. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. (2007) 357:268795. Last updated: 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. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.
COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD Genet Med. GeneReviews. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. eCollection 2022 Nov 8.
Clinical spectrum of type IV collagen (COL4A1) mutations: a novel 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. 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. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, mutations: a novel genetic multisystem disease. NCI CPTC Antibody Characterization Program. Graefe's Arch Clin Exp Ophthalmol. Treatment Epub 2014 Jan 5. 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. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. 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. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Fetal intracerebral hemorrhage and cataract: think COL4A1. It is passed through families in a autosomal dominant fashion. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. 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 The severity of the condition varies greatly among affected individuals. Arch Ophthalmol. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Bennett RL, French KS, Resta RG, Doyle DL. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. 11:827. doi: 10.3389/fneur.2020.00827. (2014) 252:178994. People listened to us and to Zeeva in a very different and proactive way. MedlinePlus also links to health information from non-government Web sites. Jeanne M, Gould DB.
COL4A1 brain small-vessel disease - Radiopaedia Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Migraines can occur with or without aura. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 2010;41:e513-518. Dr. Madsen suggested Zeeva have an operation called a 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. PMC doi: 10.1111/cge.12379, 13. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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. doi: 10.1002/ana.23736, 4. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1212/01.WNL.0000123113.46672.68, 25. This condition causes mutations in genes that produce a specific type of collagen. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 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.
Col4a1 mutation generates vascular abnormalities correlated with 10.1161/STROKEAHA.110.581918. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Suite 500 eCollection 2021. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Fax: 203-263-9938, Washington, DC Office During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Please note that NORD provides this information for the benefit of the rare disease community. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. 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. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 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). Therapies are based on the specific symptoms in each individual. NORD is a registered 501(c)(3) charity organization. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 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.