COL4A1 and COL4A2 are on Chr. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. 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. Six alpha chains of type IV. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . and transmitted securely. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. (2017) 377:111931. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. 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). Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 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. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Zeevas brain to treat a cyst in her brain caused by porencephaly. Graefe's Arch Clin Exp Ophthalmol. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Genet Med. What is the prognosis of a genetic condition? Dev Med Child Neurol. Bone. Further refinement of COL4A1 and COL4A2 related cortical malformations. doi: 10.1038/jp.2013.135, 29. (2006) 354:148996. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 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.) 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. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Written informed consent was obtained from the patient and the patient's parents for publication of this case report. It is not uncommon for an unaffected parent to have a severely affected child. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Practical approach to the diagnosis of adult-onset - BMJ (19). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. In the brain, intracerebral hemorrhage is the most frequent phenotype. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 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. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. COL4A1-related brain small-vessel disease - MedlinePlus PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. 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). CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. Fetal intracerebral hemorrhage and cataract: think COL4A1. All authors contributed to the article and approved the submitted version. This site needs JavaScript to work properly. COL4A1 mutations in patients with sporadic late-onset intracerebral This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Childhood presentation of COL4A1 mutations. N Engl J Med. Painful muscle cramps can occur and can develop before three years of age. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Disclaimer. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 2011 Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. To use the sharing features on this page, please enable JavaScript. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. (2012) 54:56974. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. (2014) 15:16. 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). These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Pathology. COL4A1 mutations as a monogenic cause of cerebral Acute urinary retention due to a novel collagen COL4A1 mutation. Neuropediatrics. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). (2014) 252:178994. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. doi: 10.1007/s00417-014-2800-6, 12. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Phone: 203-263-9938 for the triple helical CB3[IV] domain. 2010 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Disease Overview. Am J Med Genet A. Jeanne M, Gould DB. 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. Am J Med Genet. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . I cannot describe the feeling of seeing your child healed. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. 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. (2011) 42:13. What does it mean to have a COL4A1 - Little Braveheart | Facebook The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 1779 Massachusetts Avenue Neurology. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. doi: 10.1186/s12881-014-0097-2, 11. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). TTY: (866) 411-1010 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. doi: 10.1056/NEJMoa1707914, 6. Bookshelf 2012;21:R97-R110. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. The .gov means its official. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Collagen, type IV, alpha 1 - Wikipedia Arch Ophthalmol. Muscle cramps can be spontaneous or triggered by exercise. NCI CPTC Antibody Characterization Program. The COL4A1 stroke syndrome. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Please enable it to take advantage of the complete set of features! Internet. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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.
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