Phone: 617-249-7300, Danbury, CT office (2014) 11:3612. Childhood presentation of COL4A1 mutations. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. (1982) 40:5679. Changing lives of those with rare disease. Disease Overview. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). 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. What are the different ways a genetic condition can be inherited? 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 GeneReviews. Still other individuals may not develop any symptoms until well into adulthood. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. 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. Genet Med. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. doi: 10.1212/01.WNL.0000123113.46672.68, 25. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. 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. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. (2015) 88:46873. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). September 2003. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). doi: COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. doi: 10.1186/s12881-014-0097-2, 11. Pediatr Neurol. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Bone. 10.1161/STROKEAHA.110.581918. doi: 10.1038/jp.2013.135, 29. 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). 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.) She, then, developed seizures which were controlled by valproic acid. What is the prognosis of a genetic condition? The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 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. doi: 10.1056/NEJMoa1707914, 6. 2008 May;192(5):971-84; discussion 984-6. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). In people with HANAC syndrome, angiopathy affects several parts of the body. eCollection 2022. Congenital Cephalic Disorders If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. (2013) 73:4857. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. He also wanted to remove a shunt that was implanted in 30. N Engl J Med. 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. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. No microbleeds or cystic cavities were found. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. 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. 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). (2010). official website and that any information you provide is encrypted What does it mean if a disorder seems to run in my family? 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. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. https://www.ncbi.nlm.nih.gov/pubmed/26610912. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. (2008) 17:42433. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. When these ropes are secreted, they assemble into net-like structures outside the cells. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Early intervention is important in ensuring that children with reach their highest potential. N Engl J Med. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Epub 2016 Apr 24. for the triple helical CB3[IV] domain. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. Summary: It is not uncommon for an unaffected parent to have a severely affected child. Therapies are based on the specific symptoms in each individual. It is passed through families in a autosomal dominant fashion. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The severity of the condition varies greatly among affected individuals. Seattle, WA: University of Washington, Seattle; 1993-. The COL4A1 and COL4A2 genes were screened in proband IV-6. Neurol. sharing sensitive information, make sure youre on a federal 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 2012;21:R97-R110. 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. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. small vessel disease: a systematic review. doi: 10.1212/WNL.0000000000000837, 20. Autosomal Dominant Familial Porencephaly Type I. 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. She has regular physical, speech, and occupational therapy. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Disclaimer. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. It affects mainly young adults, children and more typically neonates. 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. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Some individuals develop cysts on the kidney. Danbury, CT 06810 doi: 10.1111/cge.12379, 13. The retina is the light-sensitive membrane that lines the inside of the eyes. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Fax: 203-263-9938, Washington, DC Office However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. At least six affected families have been described in the scientific literature. 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. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 2009 Jun 25 [updated 2016 Jul 7]. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Clinical Testing and Workup 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. doi: 10.1212/WNL.0000000000001309, 8. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Epub 2010 Jun 17. 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. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. Arch Neurol. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Years published: 2019. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. J Genet Couns. Ultrasound in utero from IV-6 (A). An official website of the United States government. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. MeSH Hereditary cerebral small vessel diseases: a review. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. COL4A1/A2-related disorders are dominant genetic disorders. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Contact a health care provider if you have questions about your health. doi: 10.1007/s00417-014-2800-6, 12. Front Aging Neurosci. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. 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. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Your support helps to ensure everyones free access to NORDs rare disease reports. doi: 10.1111/j.1469-8749.2011.04198.x, 26. 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.