Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. 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. January 31, 2019 Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Danbury, CT 06810 Acute urinary retention due to a novel collagen COL4A1 mutation. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Curr Opin Neurol. 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). doi: 10.1016/j.ejpn.2009.04.010, 27. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Neurology. 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. It is ubiquitously expressed in many tissues and cell types. doi: 10.1212/01.WNL.0000123113.46672.68, 25. People with HANAC syndrome develop kidney disease (nephropathy). (19). The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). In the human genome, there are 46 chromosomes. People with COL4A1-related brain small vessel disease 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). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. What are the different ways a genetic condition can be inherited? 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.) COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. We provide education, advocacy, and resources for families and individuals affected. Suite 500 Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. mutations: a novel genetic multisystem disease. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Washington, DC 20036 2010;17(13):1317-24. doi: 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). The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Prenatal clinical manifestations in individuals with COL4A1/2 variants. Phone: 617-249-7300, Danbury, CT office In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. PMC The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 2018;61:765-772. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. doi: 10.1001/archneur.1983.04050080067013, 17. The COL4A1 and COL4A2 genes were screened in proband IV-6. Ann Changing lives of those with rare disease. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. doi: 10.1016/j.matbio.2016.10.003, 23. Front. The .gov means its official. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. (2014) 252:178994. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 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 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. 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. 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. However, in people with HANAC syndrome, these aneurysms typically do not burst. Jeanne M, Gould DB. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Curr Med Chem. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 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: 10.1002/ana.23736, 4. In the brain, intracerebral hemorrhage is the most frequent phenotype. TTY: (866) 411-1010 Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 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. Standardized (15) familiar pedigree is showed in Figure 1. 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. HANAC syndrome is a rare condition, although the exact prevalence is unknown. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 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. 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. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. ACS Omega. The retina is the light-sensitive membrane that lines the inside of the eyes. Neurol. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). 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. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Congenital Cephalic Disorders Before The https:// ensures that you are connecting to the Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 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. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Neurology. This condition causes mutations in genes that produce a specific type of collagen. 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 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). Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. (2020). 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. A diagnosis can be confirmed through molecular genetic testing. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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. NORD strives to open new assistance programs as funding allows. What are the different ways a genetic condition can be inherited? Muscle cramps can be spontaneous or triggered by exercise. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Dr. Madsen suggested Zeeva have an operation called a 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. Affected individuals may have no observable symptoms or only isolated migraines with aura. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. What is the prognosis of a genetic condition? doi: 10.1186/s12881-014-0097-2, 11. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. 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. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. The number of genes implicated in epilepsy has grown rapidly in the past decade. 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. It is not uncommon for an unaffected parent to have a severely affected child. 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. Progressive cerebral atrophies in three children with COL4A1 mutations. Suite 310 Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. 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. National Center for Biotechnology Information. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. 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. eCollection 2022. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Danbury, CT 06810 All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). 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. Front Aging Neurosci. No microbleeds or cystic cavities were found. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. (2014) 83:122834. Changing lives of those with rare disease. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. The surgery 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. September 2003. Cavalin M, Mine M, Philbert M, et al. Neuropediatrics. Neurology. NORD is a registered 501(c)(3) charity organization. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. 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). Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. The COL4A2 test was negative. Epub 2016 Apr 24. How are genetic conditions treated or managed? (2014) 15:16. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 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). ClinVar; [VCV000389182.3]. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Genet Med. Clipboard, Search History, and several other advanced features are temporarily unavailable. NORD is a registered 501(c)(3) charity organization. Neurology. N Engl J Med. Hereditary cerebral small vessel diseases: a review. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. doi: 10.1056/NEJMoa1707914, 6. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Type IV collagen molecules attach to each other to form complex protein networks. Bethesda, MD 20894, Web Policies Gould Syndrome is an ultra rare genetic, multi-system disorder. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. (2004) 62:16135. GeneReviews. . 30. (2015) 88:46873. 2008 May;192(5):971-84; discussion 984-6. Childhood presentation of COL4A1 mutations. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). 1779 Massachusetts Avenue Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. percent confident in Dr. Madsen and the epilepsy team. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. People listened to us and to Zeeva in a very different and proactive way. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. The size and location of cerebral cavities contributes to clinical variability. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. COL4A1 is an essential component for basal membrane stability. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. (2010) 75:7479. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Stroke is a leading cause of death and serious long-term disability in developed nations. Last updated: doi: 10.1111/j.1469-8749.2011.04198.x, 26. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 128:4839. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. 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. (2014) 34:757. (2005) 308:116771. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. (2015) 17:84353. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. IV-3 was diagnosed with ventriculomegaly in utero. Stroke. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. doi: 10.1001/archophthalmol.2010.42, 10. II-2 had a limp since childhood attributed to forceps delivery. Years published: 2019. mutations: a novel genetic multisystem disease. 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. doi: 10.1212/WNL.0b013e3181eee440, 28. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. The information on this site should not be used as a substitute for professional medical care or advice. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. J Genet Couns. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. In the brain, intracerebral hemorrhage is the most frequent phenotype. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. (2008) 17:42433. Lenses corrected for hypermetropia. Quincy, MA 02169 Further refinement of COL4A1 and COL4A2 related cortical malformations. 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. Quincy, MA 02169 The severity of the condition varies greatly among affected individuals. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. eCollection 2022. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Axenfeld-Rieger anomaly and cataract can cause impaired vision. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). doi: 10.1038/gim.2014.210, 3. (2015) 17:40524.
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