Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Arch Ophthalmol. 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. Am J Med Genet. Phone: 202-588-5700. Gould Syndrome is an ultra rare genetic, multi-system disorder. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Nearly half of these participants were diagnosed with infantile spasms. Maybe try a search? doi: 10.1212/WNL.0b013e3181eee440, 28. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. (2006) 354:148996. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. In the brain, intracerebral hemorrhage is the most frequent phenotype. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. In most cases, an affected person has one parent with the condition. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Neuropediatrics. 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. . These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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: (2015) 88:46873. 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. What are the different ways a genetic condition can be inherited? Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. eCollection 2022. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Years published: 2019. The https:// ensures that you are connecting to the 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). 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. mutations: a novel genetic multisystem disease. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: 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. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. 1900 Crown Colony Drive The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. This condition causes mutations in genes that produce a specific type of collagen. 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.) (2007) 357:268795. my mom suggested we call Boston Childrens Hospital. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Quincy, MA 02169 An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Recent findings: Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. This site needs JavaScript to work properly. A diagnosis can be confirmed through molecular genetic testing. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Dr. Madsen suggested Zeeva have an operation called a COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (2013) 73:4857. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 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. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Science. Matrix Biol. 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. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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. It looks like nothing was found at this location. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Migraines can occur with or without aura. Epub 2014 Jan 5. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. 2010;41:e513-518. (No doctor had ever taken a call on their lunch break to speak with me). official website and that any information you provide is encrypted Clin Neurol Neurosurg. 2010;17(13):1317-24. doi: Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Firstly, it segregates within the family with the phenotype. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. eCollection 2022. Genet Med. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Dev Med Child Neurol. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. doi: 10.1136/jmg.2005.035584, 15. (2010). National Institute of Neurological Disorders and Stroke. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. (2006) 43:4905. Affected individuals may have no observable symptoms or only isolated migraines with aura. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. There are no standardized treatment protocols or guidelines for affected individuals. 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. Genet Med. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. (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). Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. 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.