At least 50 individuals with this condition have been described in the scientific literature. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. doi: 10.1212/WNL.0000000000001309, 8. doi: It is not uncommon for an unaffected parent to have a severely affected child. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. 2018;91:e2078-e2088. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Fetal intracerebral hemorrhage and cataract: think COL4A1. 8600 Rockville Pike The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. 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. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Further refinement of COL4A1 and COL4A2 related cortical malformations. eCollection 2022. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. doi: 10.2214/ajr.149.2.351, 19. How can gene variants affect health and development? If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. 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. 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). for the triple helical CB3[IV] domain. MedlinePlus also links to health information from non-government Web sites. and transmitted securely. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. doi: 10.1055/s-0031-1275343, 24. GeneReviews. doi: 10.1016/j.ejpn.2009.04.010, 27. Collagen, type IV, alpha 1 - Wikipedia Genet Med. We provide education, advocacy, and resources for families and individuals affected. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and In cases where the mutation is inherited, the carrier parent is often clinically unaffected. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Gould Syndrome is an ultra rare genetic, multi-system disorder. Neuropediatrics. (2011) 42:13. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. When these ropes are secreted, they assemble into net-like structures outside the cells. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. However, there are exceptions that depend on precisely when and where the mutation arose. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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, . 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. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. The severity of the condition varies greatly among affected individuals. Zeevas brain to treat a cyst in her brain caused by porencephaly. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. 2010 COL4A1 and COL4A2 are on Chr. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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. Summary: Seattle, WA: University of Washington, Seattle; 1993-. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Genet Med. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. 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. 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 COL4A1 gene provides instructions for making one component of a protein called type IV collagen. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 2008 May;192(5):971-84; discussion 984-6. 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. To use the sharing features on this page, please enable JavaScript. 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). Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. 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. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. A diagnosis can be confirmed through molecular genetic testing. doi: 10.1002/ajmg.10452, 18. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Epub 2016 Apr 24. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Type IV collagen molecules attach to each other to form complex protein networks. Genet Med. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Contact a health care provider if you have questions about your health. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Treatment What does it mean if a disorder seems to run in my family? 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. Fax: 203-263-9938, Washington, DC Office She has regular physical, speech, and occupational therapy. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Suite 500 https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Stroke. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Berg R, Aleck A, Kaplan A. Familial porencephaly. Plaisier E, Ronco P. COL4A1-Related Disorders. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. How are genetic conditions treated or managed? Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel 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. Jeanne M, Gould DB. TTY: (866) 411-1010 Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 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. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. 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). Rarely, new mutations in the gene occur in people with no history of the disorder in their family. (1987) 8:4216. Years published: 2019. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Front. September 2003. Arch Neurol. Nearly half of these participants were diagnosed with infantile spasms. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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. He would separate the two halves of her brain by 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. Please note that NORD provides this information for the benefit of the rare disease community. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 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.) People listened to us and to Zeeva in a very different and proactive way. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Accessibility Neurology. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 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. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 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. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. He smiled, caught it, and asked Zeeva if he could throw it back. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Firstly, it segregates within the family with the phenotype. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. NORD is a registered 501(c)(3) charity organization. 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 type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. my mom suggested we call Boston Childrens Hospital. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel If either parent also carries the mutation, it is considered inherited. N Engl J Med. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 10.2174/092986710790936293. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. She also showed severe hypermetropia. Please note that NORD provides this information for the benefit of the rare disease community. HANAC syndrome is caused by genetic changes in the COL4A1 gene. FOIA Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. PMC The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Mutations in the COL4A1 gene cause HANAC syndrome. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. doi: 10.1038/nmeth.2890, 22. (1982) 40:5679. Neurology. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al.