col4a1 syndrome life expectancy col4a1 syndrome life expectancy

Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. The signs and symptoms can manifest at almost any age from before birth to old age. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. doi: 10.1111/cge.12379, 13. Disease Overview. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Disclaimer. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Clipboard, Search History, and several other advanced features are temporarily unavailable. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 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. mutations: a novel genetic multisystem disease. It is important to discuss these concepts with a genetic counselor and understand their implications. Dev Med Child Neurol. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. 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. doi: 10.1002/ana.23736, 4. Neurology. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. 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: Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 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 . If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 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). doi: 10.1007/s10897-008-9169-9, 16. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). Danbury, CT 06810 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. 30. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Washington, DC 20036 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Bethesda, MD 20894, Web Policies TTY: (866) 411-1010 Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Phone: 617-249-7300, Danbury, CT office Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. In most cases, an affected person has one parent with the condition. IV-3 was diagnosed with ventriculomegaly in utero. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. eCollection 2022 Nov 8. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Bull Acad Natl Med. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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. She, then, developed seizures which were controlled by valproic acid. If either parent also carries the mutation, it is considered inherited. 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. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Am J Med Genet. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. What are the different ways a genetic condition can be inherited? 1900 Crown Colony Drive In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. doi: 10.1212/WNL.0000000000000837, 20. Childhood presentation of COL4A1 mutations. 2010;17(13):1317-24. doi: Gould Syndrome is a rare, genetic, multi-system disorder. Migraines can occur with or without aura. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Hum Mol Genet. Jeanne M, Gould DB. (2014) 15:16. The retina is the light-sensitive membrane that lines the inside of the eyes. seizure activity. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Probands' father had severe hypermetropia and bilateral cataracts. 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. Genet Med. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). 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. 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). Neurol. An official website of the United States government. ClinVar; [VCV000389182.3]. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Type IV collagen molecules attach to each other to form complex protein networks. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. . (2007) 357:268795. J Perinatol. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 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. He smiled, caught it, and asked Zeeva if he could throw it back. eCollection 2021. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. (2015) 17:40524. doi: 10.1212/WNL.0000000000001309, 8. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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). Figure 3. GeneReviews. Dev Med Child Neurol. 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. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. January 31, 2019 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. 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. Some individuals develop cysts on the kidney. To use the sharing features on this page, please enable JavaScript. 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. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. (2015) 17:84353. Federal government websites often end in .gov or .mil. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Berg R, Aleck A, Kaplan A. Familial porencephaly. (2006) 354:148996. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. National Center for Biotechnology Information. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Resource(s) for Medical Professionals and Scientists on This Disease: (2015) 84:91826. 1779 Massachusetts Avenue Last updated: While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. (1987) 8:4216. (2014) 83:122834. Nearly half of these participants were diagnosed with infantile spasms. In the brain, intracerebral hemorrhage is the most frequent phenotype. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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). We provide education, advocacy, and resources for families and individuals affected. 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. Phone: 202-588-5700. It affects mainly young adults, children and more typically neonates. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Various muscles can be affected and muscle strength can become weakened. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. (2014) 34:757. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. It looks like nothing was found at this location. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Curr Opin Neurol. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Mutations in the COL4A1 gene cause HANAC syndrome. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Bone. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. In most people, small vessel disease in the brain does not cause symptoms. 11:827. doi: 10.3389/fneur.2020.00827. Ophthalmological features associated with COL4A1 mutations. (2010) 14:1827. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al.