A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. He smiled, caught it, and asked Zeeva if he could throw it back. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. (2014) 34:757. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Seattle, WA: University of Washington, Seattle; 1993-. Neurol. https://www.ncbi.nlm.nih.gov/pubmed/26610912. In most cases, an affected person has one parent with the condition. Unauthorized use of these marks is strictly prohibited. He was confident this would reduce or stop the Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. N Engl J Med. Graefe's Arch Clin Exp Ophthalmol. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Summary: 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. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. HHS Vulnerability Disclosure, Help doi: 10.1038/nmeth.2890, 22. doi: 10.1111/j.1469-8749.2011.04198.x, 26. In people with HANAC syndrome, angiopathy affects several parts of the body. Berg R, Aleck A, Kaplan A. Familial porencephaly. MeSH (2010) 75:7479. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Quincy, MA 02169 PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Bennett RL, French KS, Resta RG, Doyle DL. doi: 10.1212/WNL.0b013e3181c3fd12, 9. doi: 10.1038/jp.2013.135, 29. J Perinatol. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. doi: 10.1001/archophthalmol.2010.42, 10. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. There are no standardized treatment protocols or guidelines for affected individuals. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. The size and location of cerebral cavities contributes to clinical variability. Summary. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. COL4A1/A2-related disorders are dominant genetic disorders. How are genetic conditions treated or managed? As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 1900 Crown Colony Drive COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. IV-3 was diagnosed with ventriculomegaly in utero. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Neuropediatrics. Painful muscle cramps can occur and can develop before three years of age. . These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Neurology. BMC Med Genet. Am J Med Genet A. The site is secure. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. (2020). Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. What does it mean if a disorder seems to run in my family? Science. doi: 10.1111/cge.12543. In the brain, intracerebral hemorrhage is the most frequent phenotype. doi: 10.1056/NEJMoa071906, 14. 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. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. 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. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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. (2006) 354:148996. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Please note that NORD provides this information for the benefit of the rare disease community. It looks like nothing was found at this location. 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 . GeneReviews. 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. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Muscle cramps can be spontaneous or triggered by exercise. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 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. 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. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. J Neurol Sci. 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). Genet Med. 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. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Epub 2010 Jun 17. Bethesda, MD 20894, Web Policies (1982) 40:5679. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. doi: 10.1126/science.1109418, 5. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 2009 Jun 25 [Updated 2016 Jul 7]. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. At least 50 individuals with this condition have been described in the scientific literature. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). government site. How are genetic conditions treated or managed? Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. The .gov means its official. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. (2015) 84:91826. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. Gould Syndrome is an ultra rare genetic, multi-system disorder. Arch Ophthalmol. cutting tissue called the corpus callosum, then make some additional delicate Lenses corrected for hypermetropia. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). doi: 10.1038/gim.2015.30, 21. 30. 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. National Center for Biotechnology Information. If either parent also carries the mutation, it is considered inherited. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. It is not uncommon for an unaffected parent to have a severely affected child. Probands' father had severe hypermetropia and bilateral cataracts. (2015) 17:40524. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Stroke is a leading cause of death and serious long-term disability in developed nations. N Engl J Med. Suite 500 2010 Aug;41(8):e513-8. People listened to us and to Zeeva in a very different and proactive way. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. She has regular physical, speech, and occupational therapy. Curr Opin Neurol. A diagnosis can be confirmed through molecular genetic testing. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. The COL4A1 and COL4A2 genes were screened in proband IV-6. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. An official website of the United States government. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role If we dont have a program for you now, please continue to check back with us. Epub 2022 Apr 14. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. (2014) 252:178994. Genet Med. sharing sensitive information, make sure youre on a federal (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. January 31, 2019 What does it mean if a disorder seems to run in my family? Curr Med Chem. 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. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological ( 1) [porencephaly ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological 11:827. doi: 10.3389/fneur.2020.00827. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Thats not to say Zeeva hasnt had to work hard since the surgery. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. COL4A1 is an essential component for basal membrane stability. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. (2014) 83:122834. Purpose of review: The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. The surgery doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019.
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