https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 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. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. 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). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Gould Syndrome is an ultra rare genetic, multi-system disorder. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Am J Med Genet A. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. doi: 10.1016/j.ejpn.2009.04.010, 27. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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. At least six affected families have been described in the scientific literature. She has regular physical, speech, and occupational therapy. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Bookshelf 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. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. In the brain, intracerebral hemorrhage is the most frequent phenotype. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Neurology. Eur J Paediatr Neurol. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. The surgery 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. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. How are genetic conditions treated or managed? 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. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. 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). (2009) 73:187382. IV-3 was diagnosed with ventriculomegaly in utero. Jeanne M, Gould DB. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. doi: 10.1038/nmeth.2890, 22. NORD is a registered 501(c)(3) charity organization. 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. (No doctor had ever taken a call on their lunch break to speak with me). Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Eur J Med Genet. MedlinePlus also links to health information from non-government Web sites. J Genet Couns. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 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. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Further refinement of COL4A1 and COL4A2 related cortical malformations. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. doi: 10.1007/s00417-014-2800-6, 12. N Engl J Med. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Years published: 2019. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. doi: 10.1212/WNL.0b013e3181c3fd12, 9. doi: 10.1002/ana.23736, 4. N Engl J Med. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Please note that NORD provides this information for the benefit of the rare disease community. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Nearly half of these participants were diagnosed with infantile spasms. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Probands' father had severe hypermetropia and bilateral cataracts. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 4 Both . Therapies are based on the specific symptoms in each individual. In most people, small vessel disease in the brain does not cause symptoms. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. COL4A1 and COL4A2 are on Chr. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 55 Kenosia Avenue Recent findings: MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. doi: 10.1111/j.1469-8749.2011.04198.x, 26. mutations: a novel genetic multisystem disease. 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. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. NORD strives to open new assistance programs as funding allows. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). What does it mean if a disorder seems to run in my family? Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 8600 Rockville Pike Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. NCI CPTC Antibody Characterization Program. doi: 10.1111/cge.12379, 13. (2018) 91:e207888. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. BMC Med Genet. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. doi: 10.1212/WNL.0000000000001309, 8. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. It is ubiquitously expressed in many tissues and cell types. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 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. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Neurology. 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. 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). 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Ann Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Front Aging Neurosci. September 2003. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps 55 Kenosia Avenue Neurology. doi: Phone: 203-263-9938 Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. 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. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. doi: 10.1212/WNL.0b013e3181eee440, 28. Type IV collagen molecules attach to each other to form complex protein networks. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. doi: 10.1016/j.matbio.2016.10.003, 23. Six alpha chains of type IV. COL4A1 Syndrome CADASIL COL4A1 mutations in patients with sporadic late-onset intracerebral IV-3 and IV-6 are closely followed by a neuropediatrician (VW). She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. Figure 3. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. She, then, developed seizures which were controlled by valproic acid. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. 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. doi: 10.1007/s10897-008-9169-9, 16. Type IV collagen molecules attach to each other to form complex protein networks. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. COL4A1 mutations as a monogenic cause of cerebral Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Phone: 617-249-7300, Danbury, CT office
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