Quincy, MA 02169 All authors contributed to the article and approved the submitted version. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. 2009 Jun 25 [Updated 2016 Jul 7]. Matrix Biol. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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). IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Summary: The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Autosomal Dominant Familial Porencephaly Type I. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. (2012) 54:56974. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 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. (2011) 42:13. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. doi: 10.1007/s10897-008-9169-9, 16. 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. Your support helps to ensure everyones free access to NORDs rare disease reports. 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.) cuts under the microscope. 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. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. The .gov means its official. Phone: 202-588-5700. Hereditary cerebral small vessel diseases: a review. HHS Vulnerability Disclosure, Help We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. No microbleeds or cystic cavities were found. Quincy, MA 02169 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. eCollection 2022. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. The number of genes implicated in epilepsy has grown rapidly in the past decade. Front. Careers. doi: 10.1111/cge.12379, 13. In the brain, intracerebral hemorrhage is the most frequent phenotype. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). 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 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). 2010;17(13):1317-24. doi: COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Phone: 617-249-7300, Danbury, CT office Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 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. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Figure 3. Internet. Zeevas brain to treat a cyst in her brain caused by porencephaly. Early intervention is important in ensuring that children with reach their highest potential. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 2011 How are genetic conditions treated or managed? Prenatal clinical manifestations in individuals with COL4A1/2 variants. TTY: (866) 411-1010 The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. It is not uncommon for an unaffected parent to have a severely affected child. (2002) 112:198202. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. doi: 10.1212/WNL.0000000000000837, 20. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. ACS Omega. Fax: 203-263-9938, Washington, DC Office 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. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. The COL4A1 stroke syndrome. doi: 10.1007/s00417-014-2800-6, 12. 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. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. doi: 10.1212/WNL.0000000000001309, 8. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. 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. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Phone: 202-588-5700. Suite 310 In cases where the mutation is inherited, the carrier parent is often clinically unaffected. N Engl J Med. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 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. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. doi: 10.2214/ajr.149.2.351, 19. Some individuals develop cysts on the kidney. Childhood presentation of COL4A1 mutations. MeSH Phone: 203-263-9938 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). Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. (2010). HANAC syndrome is caused by genetic changes in the COL4A1 gene. 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. Suite 310 She has regular physical, speech, and occupational therapy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Unauthorized use of these marks is strictly prohibited. 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 extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Neurology. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. She, then, developed seizures which were controlled by valproic acid. Gould Syndrome is an ultra rare genetic, multi-system disorder. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. doi: 10.1136/jmg.2005.035584, 15. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. 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. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Epub 2014 Jan 5. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. This group rarely survives beyond 2 years. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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. NORD is a registered 501(c)(3) charity organization. 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). J Med Genet. 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. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. and transmitted securely. This page is currently unavailable. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Hum Mol Genet. Doctors and researchers to bring research and medical therapeutic options to those affected. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. eCollection 2022. 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). (2014) 252:178994. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. At least 50 individuals with this condition have been described in the scientific literature. The first time he came to meet us, Zeeva threw a sock at him. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. 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. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. NORD is a registered 501(c)(3) charity organization. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. When this enzyme is elevated, it is a sign of muscle damage. Probands' father had severe hypermetropia and bilateral cataracts. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. doi: 10.1038/nmeth.2890, 22. Thats not to say Zeeva hasnt had to work hard since the surgery. doi: 10.1001/archneur.1983.04050080067013, 17. doi: 10.1038/gim.2015.30, 21. N Engl J Med. Neurology. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. When we didnt feel we had any options left for treatment, (2015) 84:91826. 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. Cavalin M, Mine M, Philbert M, et al. Ann Neurol. National Center for Biotechnology Information. What is the prognosis of a genetic condition? When these ropes are secreted, they assemble into net-like structures outside the cells. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Various muscles can be affected and muscle strength can become weakened. Maybe try a search? What does it mean if a disorder seems to run in my family? Neurol. Please enable it to take advantage of the complete set of features! (2017) 5758:2944. 2010;41:e513-518. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. BMC Med Genet. 30. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). It is important to discuss these concepts with a genetic counselor and understand their implications. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. 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 the triple helical CB3[IV] domain. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 11:827. doi: 10.3389/fneur.2020.00827. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Please note that NORD provides this information for the benefit of the rare disease community. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Zagaglia Selch C, Nisevic JR, et al. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Graefe's Arch Clin Exp Ophthalmol. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Gould Syndrome is an ultra rare genetic, multi-system disorder. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . IV-3 goes to a normal school, but special schooling is required for IV-6. Nat Methods. Clin Genet. doi: 10.1038/jp.2013.135, 29. How can gene variants affect health and development? doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. (2018) 91:e207888. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Antiinflammatory therapy with canakinumab for atherosclerotic disease. IV-3 was diagnosed with ventriculomegaly in utero. Plaisier E, Ronco P. COL4A1-Related Disorders. The size and location of cerebral cavities contributes to clinical variability.