A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. doi: 10.1056/NEJMoa053727, 7. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. J Genet Couns. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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. 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. Curr Opin Neurol. doi: 10.1212/WNL.0000000000000837, 20. This condition causes mutations in genes that produce a specific type of collagen. Please enable it to take advantage of the complete set of features! 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. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. This page is currently unavailable. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. However, in people with HANAC syndrome, these aneurysms typically do not burst. Painful muscle cramps can occur and can develop before three years of age. 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. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Washington, DC 20036 At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Phone: 617-249-7300, Danbury, CT office The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Surgery may be necessary for individuals with severe cataracts. (2017) 377:111931. People listened to us and to Zeeva in a very different and proactive way. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. COL4A1/A2-related disorders are dominant genetic disorders. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Contact a health care provider if you have questions about your health. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. MeSH 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. I cannot describe the feeling of seeing your child healed. 2012;21:R97-R110. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). No microbleeds or cystic cavities were found. Unauthorized use of these marks is strictly prohibited. PS: wrote thi paper and performed the review of the literature under the supervision of GN. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. All authors contributed to the article and approved the submitted version. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. It is important to discuss these concepts with a genetic counselor and understand their implications. Standardized (15) familiar pedigree is showed in Figure 1. Neurology. What is the prognosis of a genetic condition? 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. 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 basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. (2006) 354:148996. Still other individuals may not develop any symptoms until well into adulthood. Would you like email updates of new search results? Genet Med. 2010 Aug;41(8):e513-8. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 8600 Rockville Pike 2009 Jun 25 [updated 2016 Jul 7]. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Accessibility Disease Overview. 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. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Mutations in the COL4A1 gene cause HANAC syndrome. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. No use, distribution or reproduction is permitted which does not comply with these terms. 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). The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. It is ubiquitously expressed in many tissues and cell types. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. HANAC syndrome is a rare condition, although the exact prevalence is unknown. 4 Both . 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. doi: 10.1038/nmeth.2890, 22. doi: 10.1038/gim.2015.30, 21. It is not uncommon for an unaffected parent to have a severely affected child. 2010 Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 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). [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. In the brain, intracerebral hemorrhage is the most frequent phenotype. Affected individuals may have no observable symptoms or only isolated migraines with aura. (No doctor had ever taken a call on their lunch break to speak with me). If we dont have a program for you now, please continue to check back with us. doi: 10.1111/cge.12543. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. doi: 10.1212/WNL.0b013e3181c3fd12, 9. doi: 10.1126/science.1109418, 5. The .gov means its official. 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. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. GeneReviews. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Bethesda, MD 20894, Web Policies J Neurol Sci. 128:4839. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. doi: 10.1016/j.matbio.2016.10.003, 23. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. September 2003. Fax: 203-263-9938, Washington, DC Office In addition to porencephaly there can be other forms of damage to the brain present at birth. 10.1161/STROKEAHA.110.581918. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. 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). Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. doi: 10.1212/WNL.0000000000001309, 8. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. J Perinatol. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 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. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 COL4A1/A2-related disorders are believed to affect females and males in equal numbers. TTY: (866) 411-1010 Phone: 203-263-9938 Migraines can occur with or without aura. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. 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. Neurology. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The disorder causes many symptoms, not the least of which are strokes and epilepsy. National Center for Biotechnology Information. Last updated: (2008) 23:17. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). We provide education, advocacy, and resources for families and individuals affected. The retina is the light-sensitive membrane that lines the inside of the eyes. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 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. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Ronco P. 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. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 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. 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. People with HANAC syndrome develop kidney disease (nephropathy). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Dr. Madsen suggested Zeeva have an operation called a NCI CPTC Antibody Characterization Program. seizure activity. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 2011 We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. When these ropes are secreted, they assemble into net-like structures outside the cells. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Various muscles can be affected and muscle strength can become weakened. Federal government websites often end in .gov or .mil. 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. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. doi: 10.1001/archneur.1983.04050080067013, 17. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Phone: 202-588-5700. 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. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. She also showed severe hypermetropia. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (19). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. The risk is the same for males and females. 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. 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. The surgery Doctors and researchers to bring research and medical therapeutic options to those affected. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. How are genetic conditions treated or managed? (2009) 73:187382. 1A-B). 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. 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. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. II-2 had a limp since childhood attributed to forceps delivery. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. doi: 10.1056/NEJMoa071906, 14. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 11:827. doi: 10.3389/fneur.2020.00827. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Please note that NORD provides this information for the benefit of the rare disease community. Seattle, WA: University of Washington, Seattle; 1993-. Nearly half of these participants were diagnosed with infantile spasms. doi: 10.1001/archophthalmol.2010.42, 10. Careers. INTERNET ACS Omega. (2010) 14:1827. 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). Firstly, it segregates within the family with the phenotype. Ultrasound in utero from IV-6 (A). Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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 . Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Am J Med Genet A. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. 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. Bull Acad Natl Med. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 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, . Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%).