This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Lenses corrected for hypermetropia. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. How can gene variants affect health and development? 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. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. small vessel disease: a systematic review. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. It affects mainly young adults, children and more typically neonates. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Stroke is a leading cause of death and serious long-term disability in developed nations. Curr Opin Neurol. Arch Neurol. Nat Methods. Berg R, Aleck A, Kaplan A. Familial porencephaly. 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. His bedside manner was incredible. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. doi: 10.1212/WNL.0b013e3181eee440, 28. Unauthorized use of these marks is strictly prohibited. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Gould Syndrome is an ultra rare genetic, multi-system disorder. Zagaglia Selch C, Nisevic JR, et al. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. We provide education, advocacy, and resources for families and individuals affected. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. These exceptions are nuanced and should be discussed with a genetic counselor. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Phone: 203-263-9938 Clin Genet. Progressive cerebral atrophies in three children with COL4A1 mutations. 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. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. 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 . (2014) 83:122834. 2010 Aug;41(8):e513-8. He smiled, caught it, and asked Zeeva if he could throw it back. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 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. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. How are genetic conditions treated or managed? One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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. Curr Opin Neurol. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Suite 500 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. can also contribute. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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). Epub 2014 Jan 5. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. J Neurol Sci. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Curr Med Chem. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. The https:// ensures that you are connecting to the (2013) 73:4857. 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. Quincy, MA 02169 However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 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/, For information about clinical trials sponsored by private sources, contact: In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). It is ubiquitously expressed in many tissues and cell types. doi: 10.1007/s10897-008-9169-9, 16. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. (2015) 84:91826. Various muscles can be affected and muscle strength can become weakened. It affects mainly young adults, children and more typically neonates. Pathology. doi: 10.1111/cge.12379, 13. 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). What is the prognosis of a genetic condition? ClinVar; [VCV000389182.3]. Affected individuals may have no observable symptoms or only isolated migraines with aura. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Genet Med. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Gould Syndrome is a rare, genetic, multi-system disorder. The COL4A2 test was negative. This page is currently unavailable. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Autosomal Dominant Familial Porencephaly Type I. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). doi: 10.1111/j.1469-8749.2011.04198.x, 26. The retina is the light-sensitive membrane that lines the inside of the eyes. Resource(s) for Medical Professionals and Scientists on This Disease: National Center for Biotechnology Information. (2009) 73:187382. No microbleeds or cystic cavities were found. 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). However, there are exceptions that depend on precisely when and where the mutation arose. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 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%). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. cuts under the microscope. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Thats not to say Zeeva hasnt had to work hard since the surgery. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. While there are other explanations, parental mosaicism should be considered. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. (2010). The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Pediatr Neurol. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. What does it mean if a disorder seems to run in my family? The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. doi: 10.1186/s12881-014-0097-2, 11. This is called genotype-phenotype correlation. doi: 10.1007/s00417-014-2800-6, 12. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. COL4A1 Syndrome CADASIL Graefe's Arch Clin Exp Ophthalmol. Autosomal Dominant Brain Small Vessel Disease. Muscle cramps can be spontaneous or triggered by exercise. Neurology. The severity of the condition varies greatly among affected individuals. Danbury, CT 06810 2012;21:R97-R110. National Institute of Neurological Disorders and Stroke. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 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. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. How can gene variants affect health and development? III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Dr. Madsen suggested Zeeva have an operation called a Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. The .gov means its official. eCollection 2022 Nov 8. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. doi: 10.1212/WNL.0000000000000837, 20. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. INTERNET (2014) 252:178994. Neurology. 55 Kenosia Avenue In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. Seattle, WA: University of Washington, Seattle; 1993-. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. N Engl J Med. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. Matrix Biol. Bull Acad Natl Med. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. COL4A1 mutations as a monogenic cause of cerebral Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. This condition causes mutations in genes that produce a specific type of collagen. Various treatments have been reported in the medical literature as part of single case reports or small series of patients.