Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. What are the different ways a genetic condition can be inherited? Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. It is not uncommon for an unaffected parent to have a severely affected child. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. seizure activity. 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 . HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. What are the different ways a genetic condition can be inherited? Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Genet Med. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. N Engl J Med. HHS Vulnerability Disclosure, Help A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Front Aging Neurosci. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Recent findings: PS: wrote thi paper and performed the review of the literature under the supervision of GN. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Washington, DC 20036 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 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. There are no standardized treatment protocols or guidelines for affected individuals. 1900 Crown Colony Drive Acute urinary retention due to a novel collagen COL4A1 mutation. 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 (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). (1982) 40:5679. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Early intervention is important in ensuring that children with reach their highest potential. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 11:827. doi: 10.3389/fneur.2020.00827. She, then, developed seizures which were controlled by valproic acid. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 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). COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. It is important to discuss these concepts with a genetic counselor and understand their implications. Neurol. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. (2014) 11:3612. Lenses corrected for hypermetropia. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. eCollection 2022. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Copyright 2023 by Gould Syndrome Foundation -. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 2008 May;192(5):971-84; discussion 984-6. Dev Med Child Neurol. 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. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. What does it mean if a disorder seems to run in my family? 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. 2009 Jun 25 [updated 2016 Jul 7]. 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. TTY: (866) 411-1010 Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. 2010;41:e513-518. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. I cannot describe the feeling of seeing your child healed. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. To use the sharing features on this page, please enable JavaScript. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Danbury, CT 06810 Years published: 2019. Summary. In most people, small vessel disease in the brain does not cause symptoms. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. All authors contributed to the article and approved the submitted version. 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). The size and location of cerebral cavities contributes to clinical variability. 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). Contact a health care provider if you have questions about your health. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. can also contribute. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. The retina is the light-sensitive membrane that lines the inside of the eyes. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Written informed consent was obtained from the patient and the patient's parents for publication of this case report. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. (2020). COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. (2017) 5758:2944. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Gould Syndrome is an ultra rare genetic, multi-system disorder. FOIA Berg R, Aleck A, Kaplan A. Familial porencephaly. Neuropediatrics. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Epub 2010 Jun 17. Fax: 203-263-9938, Washington, DC Office Fax: 203-263-9938, Washington, DC Office Suite 310 Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. The information on this site should not be used as a substitute for professional medical care or advice. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. doi: doi: 10.1056/NEJMoa1707914, 6. However, there are exceptions that depend on precisely when and where the mutation arose. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. In most cases, an affected person has one parent with the condition. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Am J Med Genet. (1987) 8:4216. Autosomal Dominant Brain Small Vessel Disease. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. People with HANAC syndrome develop kidney disease (nephropathy). Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 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. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. While there are other explanations, parental mosaicism should be considered. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 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, . (2006) 43:4905. Bone. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. (No doctor had ever taken a call on their lunch break to speak with me). Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Maybe try a search? The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. (18) and Staals et al. 55 Kenosia Avenue Clinical Testing and Workup J Perinatol. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Hum Mol Genet. 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. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Surgery may be necessary for individuals with severe cataracts. Facebook: https://www.facebook.com/Col4A1Foundation Please Note IV-3 goes to a normal school, but special schooling is required for IV-6. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). 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. Painful muscle cramps can occur and can develop before three years of age. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). mutations: a novel genetic multisystem disease. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Understanding what it has taken to get her to this point, though, is close to unimaginable. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 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 type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. National Center for Biotechnology Information. 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. The risk is the same for males and females. cutting tissue called the corpus callosum, then make some additional delicate doi: 10.1007/s00417-014-2800-6, 12. 2011 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. 2010 Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. doi: 10.1055/s-0031-1275343, 24. Type IV collagen molecules attach to each other to form complex protein networks. Phone: 203-263-9938 No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. 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. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. doi: 10.1126/science.1109418, 5. No microbleeds or cystic cavities were found. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Science. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Zagaglia Selch C, Nisevic JR, et al. Seattle, WA: University of Washington, Seattle; 1993-. The number of genes implicated in epilepsy has grown rapidly in the past decade. This site needs JavaScript to work properly. 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. doi: 10.1038/nmeth.2890, 22. Bull Acad Natl Med. and transmitted securely. Progressive cerebral atrophies in three children with COL4A1 mutations. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. 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. How are genetic conditions treated or managed? COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Migraines can occur with or without aura. These exceptions are nuanced and should be discussed with a genetic counselor. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. If either parent also carries the mutation, it is considered inherited. Ann Neurol. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 128:4839. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. farewell message to my late husband, people playground head transplant,
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