How can gene variants affect health and development? Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 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. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Accessibility Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Am J Med Genet A. Type IV collagen molecules attach to each other to form complex protein networks. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. COL4A1 and COL4A2 are on Chr. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Neurol. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the doi: 10.1111/j.1469-8749.2011.04198.x, 26. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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. mutations: a novel genetic multisystem disease. Six alpha chains of type IV. functional hemispherectomy. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. IV-3 was diagnosed with ventriculomegaly in utero. COL4A1/A2-related disorders are dominant genetic disorders. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. doi: 10.2214/ajr.149.2.351, 19. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. doi: Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Graefe's Arch Clin Exp Ophthalmol. 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: This condition causes mutations in genes that produce a specific type of collagen. 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. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 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. Before At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. seizure activity. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. I cannot describe the feeling of seeing your child healed. The site is secure. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. 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. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Figure 3. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare In people with HANAC syndrome, angiopathy affects several parts of the body. National Library of Medicine 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. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. NORD strives to open new assistance programs as funding allows. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. and transmitted securely. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Science. 2008 May;192(5):971-84; discussion 984-6. 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. While there are other explanations, parental mosaicism should be considered. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. It is important to discuss these concepts with a genetic counselor and understand their implications. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. In most cases, an affected person has one parent with the condition. Some individuals develop cysts on the kidney. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 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. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. The COL4A1 stroke syndrome. Phone: 203-263-9938 Clinical spectrum of type IV collagen (COL4A1) mutations: a novel Col4a1 mutation generates vascular abnormalities correlated with Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. doi: 10.1056/NEJMoa071906, 14. (1987) 8:4216. doi: 10.1007/s00417-014-2800-6, 12. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: doi: 10.1038/jp.2013.135, 29. 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. PMC 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. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . NCI CPTC Antibody Characterization Program. ACS Omega. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 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. People listened to us and to Zeeva in a very different and proactive way. Ann (18) and Staals et al. Treatment The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Neurology. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. doi: 10.1002/ajmg.10452, 18. 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. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. 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). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Firstly, it segregates within the family with the phenotype. Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. (1982) 40:5679. Clinical Testing and Workup 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). Plaisier E, Ronco P. COL4A1-Related Disorders. What does it mean if a disorder seems to run in my family? Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. A diagnosis can be confirmed through molecular genetic testing. Bull Acad Natl Med. doi: 10.1186/s12881-014-0097-2, 11. (2005) 308:116771. Curr Opin Neurol. COL4A1 is an essential component for basal membrane stability. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Genet Med. Painful muscle cramps can occur and can develop before three years of age. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Please note that NORD provides this information for the benefit of the rare disease community. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. COL4A1 Syndrome CADASIL If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. The severity of the condition varies greatly among affected individuals. II-2 had a limp since childhood attributed to forceps delivery. Pathology. The surgery The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. This condition causes mutations in genes that produce a specific type of collagen. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). (2007) 357:268795. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Antiinflammatory therapy with canakinumab for atherosclerotic disease. The disorder causes many symptoms, not the least of which are strokes and epilepsy. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and 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). This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. (2006) 354:148996. In the human genome, there are 46 chromosomes. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 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. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 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. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Early intervention is important in ensuring that children with reach their highest potential. can also contribute. 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. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Fetal intracerebral hemorrhage and cataract: think COL4A1. doi: 10.1007/s10897-008-9169-9, 16. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Further refinement of COL4A1 and COL4A2 related cortical malformations. 2018;91:e2078-e2088. 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. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Maybe try a search? doi: 10.1212/WNL.0000000000000837, 20. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Phone: 203-263-9938 For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Progressive cerebral atrophies in three children with COL4A1 mutations. The retina is the light-sensitive membrane that lines the inside of the eyes. 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. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Thats not to say Zeeva hasnt had to work hard since the surgery. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. doi: 10.1212/WNL.0000000000001309, 8. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 8600 Rockville Pike 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. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. In the brain, intracerebral hemorrhage is the most frequent phenotype. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Am J Med Genet. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. What does it mean to have a COL4A1 - Little Braveheart | Facebook Contact a health care provider if you have questions about your health. The https:// ensures that you are connecting to the Individuals with HANAC syndrome also experience a variety of eye problems. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. government site. 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. 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. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Neurol. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. 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. Changing lives of those with rare disease. Therapies are based on the specific symptoms in each individual. What does it mean if a disorder seems to run in my family? Genet Med. 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.
Pollo Tropical Soup Recipe, 1011 Twin Flame Reunion, Articles C