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. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. There are no standardized treatment protocols or guidelines for affected individuals. It looks like nothing was found at this location. Eur J Med Genet. We provide education, advocacy, and resources for families and individuals affected. 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. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 2010 Aug;41(8):e513-8. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 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. When these ropes are secreted, they assemble into net-like structures outside the cells. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. No use, distribution or reproduction is permitted which does not comply with these terms. (2012) 54:56974. It is ubiquitously expressed in many tissues and cell types. doi: 10.1186/s12881-014-0097-2, 11. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. How can gene variants affect health and development? Neuropediatrics. (2010) 14:1827. Acute urinary retention due to a novel collagen COL4A1 mutation. 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.) The COL4A1 stroke syndrome. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). What does it mean if a disorder seems to run in my family? Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 30. 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. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Years published: 2019. Phone: 203-263-9938 55 Kenosia Avenue Pathology. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. He smiled, caught it, and asked Zeeva if he could throw it back. N Engl J Med. In addition to porencephaly there can be other forms of damage to the brain present at birth. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. (1982) 40:5679. (18) and Staals et al. doi: 10.1056/NEJMoa1707914, 6. 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. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. About half of people with this condition 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). Science. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. 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. (2006) 43:4905. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. It affects mainly young adults, children and more typically neonates. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Six alpha chains of type IV. doi: 10.1111/cge.12379, 13. 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. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. This is called genotype-phenotype correlation. 1900 Crown Colony Drive Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 2011 COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. doi: 10.1212/WNL.0b013e3181c3fd12, 9. The severity of the condition varies greatly among affected individuals. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. government site. What does it mean if a disorder seems to run in my family? 55 Kenosia Avenue 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. (No doctor had ever taken a call on their lunch break to speak with me). However, there are exceptions that depend on precisely when and where the mutation arose. my mom suggested we call Boston Childrens Hospital. Please enable it to take advantage of the complete set of features! Neurology. (2002) 112:198202. 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). 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). 8600 Rockville Pike (2018) 91:e207888. Zeevas brain to treat a cyst in her brain caused by porencephaly. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Lanfranconi S, Markus HS. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Matrix Biol. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. doi: 10.1212/WNL.0000000000000837, 20. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). The surgery Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. However, in people with HANAC syndrome, these aneurysms typically do not burst. Front. 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). 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). seizure activity. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Therapies are based on the specific symptoms in each individual. Suite 500 The .gov means its official. No microbleeds or cystic cavities were found. J Genet Couns. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. (19). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Would you like email updates of new search results? Nat Methods.