1900 Crown Colony Drive J Neurol Sci. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Ophthalmological features associated with COL4A1 mutations. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. When these ropes are secreted, they assemble into net-like structures outside the cells. In most people, small vessel disease in the brain does not cause symptoms. In most cases, an affected person has one parent with the condition. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Autosomal Dominant Brain Small Vessel Disease. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Epub 2014 Jan 5. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. 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. 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. The information on this site should not be used as a substitute for professional medical care or advice. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. It affects mainly young adults, children and more typically neonates. Clinical Testing and Workup Mutations in the COL4A1 gene cause HANAC syndrome. (2015) 17:84353. eCollection 2022 Nov 8. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 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. Firstly, it segregates within the family with the phenotype. 1779 Massachusetts Avenue What are the different ways a genetic condition can be inherited? Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. 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. 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. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. doi: 10.1056/NEJMoa071906, 14. 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). Neurology. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Curr Opin Neurol. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. N Engl J Med. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. doi: 10.1212/WNL.0000000000000837, 20. 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. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Progressive cerebral atrophies in three children with COL4A1 mutations. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. 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. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Epub 2016 Apr 24. 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. Neurology. Congenital Cephalic Disorders The severity of the condition varies greatly among affected individuals. His bedside manner was incredible. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Clipboard, Search History, and several other advanced features are temporarily unavailable. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. (18) and Staals et al. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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). He would separate the two halves of her brain by Dev Med Child Neurol. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 30. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. 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. 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. Contact a health care provider if you have questions about your health. Neurology. doi: 10.1016/j.matbio.2016.10.003, 23. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Stroke. Washington, DC 20036 Painful muscle cramps can occur and can develop before three years of age. September 2003. What is the prognosis of a genetic condition? Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. 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. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. It is not uncommon for an unaffected parent to have a severely affected child. doi: 10.1002/ajmg.10452, 18. Would you like email updates of new search results? 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). COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. 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. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Ann Neurol. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. She has regular physical, speech, and occupational therapy. Copyright 2023 by Gould Syndrome Foundation -. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 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. 2009 Jun 25 [Updated 2016 Jul 7]. 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. (2011) 42:13. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). The COL4A2 test was negative. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Affected individuals may have no observable symptoms or only isolated migraines with aura. doi: 10.1038/gim.2014.210, 3. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. She, then, developed seizures which were controlled by valproic acid. 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. 55 Kenosia Avenue (2015) 84:91826. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. (2007) 357:268795. However, in people with HANAC syndrome, these aneurysms typically do not burst. This is called genotype-phenotype correlation. She also showed severe hypermetropia. (2013) 73:4857. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Maybe try a search? TTY: (866) 411-1010 Thats not to say Zeeva hasnt had to work hard since the surgery. Zeevas brain to treat a cyst in her brain caused by porencephaly. MeSH 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. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. Front Aging Neurosci. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Dev Med Child Neurol. 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. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. The COL4A1 stroke syndrome. 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. Treatment Further refinement of COL4A1 and COL4A2 related cortical malformations. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Jeanne M, Gould DB.
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