When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Bethesda, MD 20894, Web Policies TTY: (866) 411-1010 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. Accessibility 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). Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. PMC (2008) 17:42433. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Clin Neurol Neurosurg. ACS Omega. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. doi: 10.1126/science.1109418, 5. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Probands' father had severe hypermetropia and bilateral cataracts. This group rarely survives beyond 2 years. Axenfeld-Rieger anomaly and cataract can cause impaired vision. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Neurology. Figure 3. Teaching families how to advocate for their loved ones and access medical information. Early intervention is important in ensuring that children with reach their highest potential. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. doi: 10.1016/j.ejpn.2009.04.010, 27. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. my mom suggested we call Boston Childrens Hospital. HHS Vulnerability Disclosure, Help cuts under the microscope. 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. 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. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. doi: 10.1186/s12881-014-0097-2, 11. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 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. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. National Institute of Neurological Disorders and Stroke. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. What are the different ways a genetic condition can be inherited? Suite 500 Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. National Center for Biotechnology Information. 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). Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 2009 Jun 25 [Updated 2016 Jul 7]. Ophthalmological features associated with COL4A1 mutations. Cavalin M, Mine M, Philbert M, et al. Berg R, Aleck A, Kaplan A. Familial porencephaly. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 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. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. (2010) 14:1827. In the human genome, there are 46 chromosomes. Changing lives of those with rare disease. Gould Syndrome is an ultra rare genetic, multi-system disorder. In the human genome, there are 46 chromosomes. Suite 500 Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. He was confident this would reduce or stop the Ann Neurol. How can gene variants affect health and development? Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Quincy, MA 02169 Ann Neurol. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. doi: 10.1038/gim.2014.210, 3. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 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. The site is secure. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Surgery may be necessary for individuals with severe cataracts. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. (2014) 11:3612. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Resource(s) for Medical Professionals and Scientists on This Disease: Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Copyright 2023 by Gould Syndrome Foundation -. 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. (2009) 73:187382. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Lenses corrected for hypermetropia. Acute urinary retention due to a novel collagen COL4A1 mutation. doi: 10.1212/WNL.0000000000000837, 20. A diagnosis can be confirmed through molecular genetic testing. It affects mainly young adults, children and more typically neonates. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, The number of genes implicated in epilepsy has grown rapidly in the past decade. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. N Engl J Med. It is ubiquitously expressed in many tissues and cell types. 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). The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. The COL4A2 test was negative. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 1900 Crown Colony Drive Dev Med Child Neurol. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Graefe's Arch Clin Exp Ophthalmol. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Am J Med Genet. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Fax: 203-263-9938, Washington, DC Office eCollection 2022 Nov 8. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Stroke. doi: 10.1056/NEJMoa071906, 14. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). 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. doi: 10.1002/ana.23736, 4. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1136/jmg.2005.035584, 15. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). eCollection 2022. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Pediatr Neurol. Phone: 617-249-7300, Danbury, CT office The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Childhood presentation of COL4A1 mutations. Clin Genet. Last updated: We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. (2006) 43:4905. mutations: a novel genetic multisystem disease. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 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. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Cereb Circ Cogn Behav. 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 Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Please note that NORD provides this information for the benefit of the rare disease community. 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. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). How are genetic conditions treated or managed? Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. Neurology. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Ultrasound in utero from IV-6 (A). Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. cutting tissue called the corpus callosum, then make some additional delicate In most cases, an affected person has one parent with the condition. The information on this site should not be used as a substitute for professional medical care or advice. 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. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). 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. No use, distribution or reproduction is permitted which does not comply with these terms. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Neurol. Suite 310 Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. (2006) 354:148996. (2004) 62:16135. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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. She also showed severe hypermetropia. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. doi: 10.1212/WNL.0000000000001309, 8. Therapies are based on the specific symptoms in each individual. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. BMC Med Genet. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 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). Washington, DC 20036 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. can also contribute. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging.
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