No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. 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. It looks like nothing was found at this location. 2018;91:e2078-e2088. 4 Both . Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Clin Genet. 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. Fax: 203-263-9938, Washington, DC Office Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Phone: 203-263-9938 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The risk is the same for males and females. 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 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Childhood presentation of COL4A1 mutations. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. doi: 10.1111/cge.12543. 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). Ann Neurol. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. It is ubiquitously expressed in many tissues and cell types. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. MeSH Please note that NORD provides this information for the benefit of the rare disease community. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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). 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. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Zeevas brain to treat a cyst in her brain caused by porencephaly. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The number of genes implicated in epilepsy has grown rapidly in the past decade. Last updated: In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . 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. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Front Aging Neurosci. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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. for the triple helical CB3[IV] domain. In most people, small vessel disease in the brain does not cause symptoms. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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). It affects mainly young adults, children and more typically neonates. Genet Med. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Clinical Testing and Workup official website and that any information you provide is encrypted Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Plaisier E, Ronco P. COL4A1-Related Disorders. Autosomal Dominant Brain Small Vessel Disease. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. To use the sharing features on this page, please enable JavaScript. doi: 10.2214/ajr.149.2.351, 19. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. She has regular physical, speech, and occupational therapy. People listened to us and to Zeeva in a very different and proactive way. COL4A1 mutations as a monogenic cause of cerebral (2014) 252:178994. Recent findings: (2008) 17:42433. Neurology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. 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). Changing lives of those with rare disease. Nat Methods. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. The site is secure. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Type IV collagen molecules attach to each other to form complex protein networks. If either parent also carries the mutation, it is considered inherited. Mutations in the COL4A1 gene cause HANAC syndrome. 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. 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. 2010 doi: 10.1111/cge.12379, 13. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. The https:// ensures that you are connecting to the 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. . PV and VW followed the children at the Neuropediatrics clinic of the same hospital. doi: 10.1038/nmeth.2890, 22. 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. Fetal intracerebral hemorrhage and cataract: think COL4A1. Migraines can occur with or without aura. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Phone: 202-588-5700. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 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). Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. 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. (2017) 5758:2944. Quincy, MA 02169 Internet. Please enable it to take advantage of the complete set of features! Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 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). eCollection 2022. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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. 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). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Purpose of review: NORD is a registered 501(c)(3) charity organization. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. 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. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. (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). cutting tissue called the corpus callosum, then make some additional delicate No microbleeds or cystic cavities were found. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. When we didnt feel we had any options left for treatment, Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). One patient (IV-3) was treated for spasticity and seizures with valproic acid. All authors contributed to the article and approved the submitted version. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. The information on this site should not be used as a substitute for professional medical care or advice. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. (2015) 88:46873. At least 50 individuals with this condition have been described in the scientific literature. doi: 10.1001/archneur.1983.04050080067013, 17. (1987) 8:4216. The COL4A1 stroke syndrome. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. National Library of Medicine Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Neurology. Changing lives of those with rare disease. Neurol. 2012;21:R97-R110. A diagnosis can be confirmed through molecular genetic testing. Epub 2016 Apr 24. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Various muscles can be affected and muscle strength can become weakened. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. This condition causes mutations in genes that produce a specific type of collagen. Seattle, WA: University of Washington, Seattle; 1993-. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). doi: 10.1136/jmg.2005.035584, 15. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. It affects mainly young adults, children and more typically neonates. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 55 Kenosia Avenue Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. (2017) 377:111931. Zagaglia Selch C, Nisevic JR, et al. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. (19). HANAC syndrome is caused by genetic changes in the COL4A1 gene. (2007) 357:268795. 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. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands).

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