Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, doi: 10.1038/nmeth.2890, 22. Antiinflammatory therapy with canakinumab for atherosclerotic disease. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Agenesis of the Corpus Callosum | National Institute of Neurological Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. 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, . Hum Mol Genet. (1987) 8:4216. Surgery may be necessary for individuals with severe cataracts. An official website of the United States government. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. The https:// ensures that you are connecting to the Six alpha chains of type IV. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Ann Neurol. He smiled, caught it, and asked Zeeva if he could throw it back. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Finding the best care for Zeeva - Boston Children's Answers Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Neurology. 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. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Neurology. He would separate the two halves of her brain by Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 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%). Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Fax: 203-263-9938, Washington, DC Office The retina is the light-sensitive membrane that lines the inside of the eyes. NCI CPTC Antibody Characterization Program. 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. Danbury, CT 06810 Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. (2010) 75:7479. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Firstly, it segregates within the family with the phenotype. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 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. 2010;41:e513-518. J Neurol Sci. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Cereb Circ Cogn Behav. (2005) 308:116771. It is passed through families in a autosomal dominant fashion. N Engl J Med. eCollection 2022 Nov 8. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. doi: 10.1002/ana.23736, 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. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. COL4A1 -Related Disorders - PubMed (2004) 62:16135. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 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. 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. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 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. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature Please enable it to take advantage of the complete set of features! COL4A1-related brain small-vessel disease - MedlinePlus 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. What does it mean if a disorder seems to run in my family? Orphanet: HANAC syndrome came with risks and was the hardest decision we had ever faced, yet we felt 100 The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. cuts under the microscope. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). IV-3 and IV-6 are closely followed by a neuropediatrician (VW). NORD strives to open new assistance programs as funding allows. Am J Med Genet A. COL4A1 and COL4A2 are on Chr. 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. Collagen, type IV, alpha 1 - Wikipedia Danbury, CT 06810 Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Summary: (2017) 5758:2944. IV-3 was diagnosed with ventriculomegaly in utero. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Pathology. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. In most cases, an affected person has one parent with the condition. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). The COL4A1 stroke syndrome. Years published: 2019. These genes are the blueprints for two proteins that wind together like a long rope inside cells. It looks like nothing was found at this location. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Neurology. 2010 https://www.ncbi.nlm.nih.gov/pubmed/26610912. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. MeSH Fax: 203-263-9938, Washington, DC Office Graefe's Arch Clin Exp Ophthalmol. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. 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. doi: 10.1111/cge.12543. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 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. (2015) 17:40524. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). 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. Nat Methods. 2012;21:R97-R110. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Gould Syndrome is an ultra rare genetic, multi-system disorder. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. He was confident this would reduce or stop the doi: 10.1212/01.WNL.0000123113.46672.68, 25. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. People listened to us and to Zeeva in a very different and proactive way. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. 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. 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). 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. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. (2013) 73:4857. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 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). Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Am J Med Genet. No microbleeds or cystic cavities were found. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. doi: 10.1002/ajmg.10452, 18. doi: 10.1212/WNL.0b013e3181eee440, 28. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Neurol. Changing lives of those with rare disease. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. 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. Internet. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Disclaimer. 1779 Massachusetts Avenue Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). (2015) 17:84353. doi: 10.1126/science.1109418, 5. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. (2014) 11:3612. 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. Neurology. mutations: a novel genetic multisystem disease. 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/.