It looks like nothing was found at this location. Eur J Paediatr Neurol. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. It is ubiquitously expressed in many tissues and cell types. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. COL4A1 and COL4A2 are on Chr. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In people with HANAC syndrome, angiopathy affects several parts of the body. 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. If we dont have a program for you now, please continue to check back with us. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Neurologic phenotypes associated with COL4A1/2 mutations 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, . The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Fax: 203-263-9938, Washington, DC Office Gould Syndrome is often 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. Phone: 617-249-7300, Danbury, CT office PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. Gould Syndrome is an ultra rare genetic, multi-system disorder. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. doi: 10.1001/archophthalmol.2010.42, 10. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Jeanne M, Gould DB. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. Neurol. doi: 10.1002/ana.23736, 4. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. IV-3 was diagnosed with ventriculomegaly in utero. Am J Med Genet. COL4A1 mutations in patients with sporadic late-onset intracerebral 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. (2009) 73:187382. If either parent also carries the mutation, it is considered inherited. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Genet Med. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. 128:4839. percent confident in Dr. Madsen and the epilepsy team. Ann Neurol. N Engl J Med. 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/. Neuropediatrics. Muscle cramps can be spontaneous or triggered by exercise. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. To use the sharing features on this page, please enable JavaScript. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Front. doi: 10.1016/j.matbio.2016.10.003, 23. Progressive cerebral atrophies in three children with COL4A1 mutations. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. II-2 had a limp since childhood attributed to forceps delivery. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Berg R, Aleck A, Kaplan A. Familial porencephaly. His bedside manner was incredible. Migraines can occur with or without aura. doi: 10.1038/jp.2013.135, 29. (2006) 354:148996. Further refinement of COL4A1 and COL4A2 related cortical malformations. 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 Childhood presentation of COL4A1 mutations. The surgery 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. Orphanet: HANAC syndrome 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. (2010) 14:1827. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). Standardized (15) familiar pedigree is showed in Figure 1. The size and location of cerebral cavities contributes to clinical variability. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke 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 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.) Treatment Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. 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%). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. The signs and symptoms can manifest at almost any age from before birth to old age. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. doi: 10.1007/s00417-014-2800-6, 12. 30. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Neurology. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. This condition causes mutations in genes that produce a specific type of collagen. How can gene variants affect health and development? Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. This is called genotype-phenotype correlation. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. cutting tissue called the corpus callosum, then make some additional delicate Teaching families how to advocate for their loved ones and access medical information. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Your support helps to ensure everyones free access to NORDs rare disease reports. doi: 10.1001/archneur.1983.04050080067013, 17. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Congenital Cephalic Disorders The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Mutations in the COL4A1 gene cause HANAC syndrome. IV-3 goes to a normal school, but special schooling is required for IV-6. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. (2007) 357:268795. 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. In the human genome, there are 46 chromosomes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. People listened to us and to Zeeva in a very different and proactive way. Ophthalmological features associated with COL4A1 mutations. It affects mainly young adults, children and more typically neonates. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome 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. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. eCollection 2022. COL4A1/A2-related disorders are dominant genetic disorders. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. 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). The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Arch Neurol. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature The first time he came to meet us, Zeeva threw a sock at him. In most cases, an affected person has one parent with the condition. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Neurology. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Suite 310 COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD 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). Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: J Perinatol. Agenesis of the Corpus Callosum | National Institute of Neurological Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Cephalic Disorders Fact Sheet. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, 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. Pathology. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Graefe's Arch Clin Exp Ophthalmol. (2014) 34:757. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Clin Neurol Neurosurg. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, PMC 2008 May;192(5):971-84; discussion 984-6. 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. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2015) 17:84353. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Thats not to say Zeeva hasnt had to work hard since the surgery. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Summary. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Neurology. Neurology. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Epilepsy and related challenges in children with COL4A1 and - PubMed Phone: 203-263-9938 All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. September 2003. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Curr Med Chem. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Washington, DC 20036 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. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 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). If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Contact a health care provider if you have questions about your health. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. NCI CPTC Antibody Characterization Program. doi: 10.1056/NEJMoa071906, 14. Autosomal Dominant Familial Porencephaly Type I. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. 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. 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). doi: 10.1111/cge.12543. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 2009 Jun 25 [Updated 2016 Jul 7]. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. (2008) 17:42433. Dr. Madsen suggested Zeeva have an operation called a doi: 10.1002/ajmg.10452, 18. (2018) 91:e207888. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) MedlinePlus also links to health information from non-government Web sites. 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. He would separate the two halves of her brain by What are the different ways a genetic condition can be inherited? Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. HHS Vulnerability Disclosure, Help (2010). Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The retina is the light-sensitive membrane that lines the inside of the eyes. 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. People with HANAC syndrome develop kidney disease (nephropathy). The disorder causes many symptoms, not the least of which are strokes and epilepsy. sharing sensitive information, make sure youre on a federal He was confident this would reduce or stop the Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. TTY: (866) 411-1010