Suite 310 The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. (2007) 357:268795. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. (2010) 75:7479. Suite 500 When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. IV-3 was diagnosed with ventriculomegaly in utero. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 1779 Massachusetts Avenue Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. doi: 10.1212/WNL.0000000000001309, 8. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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). Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Would you like email updates of new search results? Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 2012;21:R97-R110. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. How are genetic conditions treated or managed? (2012) 54:56974. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. cutting tissue called the corpus callosum, then make some additional delicate doi: 10.1038/gim.2014.210, 3. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Maybe try a search? Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 2010 COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. These exceptions are nuanced and should be discussed with a genetic counselor. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 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 . doi: 10.1038/nmeth.2890, 22. No microbleeds or cystic cavities were found. (No doctor had ever taken a call on their lunch break to speak with me). 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. Phone: 203-263-9938 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. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Neurology. In the human genome, there are 46 chromosomes. What are the different ways a genetic condition can be inherited? PV and VW followed the children at the Neuropediatrics clinic of the same hospital. doi: 10.1002/ana.23736, 4. Genet Med. 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. 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. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. In most people, small vessel disease in the brain does not cause symptoms. doi: 10.1056/NEJMoa1707914, 6. Curr Med Chem. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Type IV collagen molecules attach to each other to form complex protein networks. Phone: 202-588-5700. 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: As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Purpose of review: 55 Kenosia Avenue Phone: 617-249-7300, Danbury, CT office People listened to us and to Zeeva in a very different and proactive way. 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. 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). The information on this site should not be used as a substitute for professional medical care or advice. 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). Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. At least 50 individuals with this condition have been described in the scientific literature. 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. 2011 Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Fax: 203-263-9938, Washington, DC Office Careers. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. In most cases, an affected person has one parent with the condition. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 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. Lenses corrected for hypermetropia. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Progressive cerebral atrophies in three children with COL4A1 mutations. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. 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. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). doi: 10.1001/archneur.1983.04050080067013, 17. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. doi: 10.1016/j.matbio.2016.10.003, 23. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. percent confident in Dr. Madsen and the epilepsy team. He also wanted to remove a shunt that was implanted in Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Stroke. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Antiinflammatory therapy with canakinumab for atherosclerotic disease. National Library of Medicine For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). and transmitted securely. Gould Syndrome is an ultra rare genetic, multi-system disorder. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The retina is the light-sensitive membrane that lines the inside of the eyes. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. The COL4A2 test was negative. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Am J Med Genet A. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. MedlinePlus also links to health information from non-government Web sites. What is the prognosis of a genetic condition? She also showed severe hypermetropia. When this enzyme is elevated, it is a sign of muscle damage. 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. (2015) 17:84353. 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, . She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Zeevas brain to treat a cyst in her brain caused by porencephaly. eCollection 2021. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. doi: 10.1056/NEJMoa053727, 7. 2010;17(13):1317-24. doi: 1A-B). 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. 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). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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).