The site is secure. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. (2011) 42:13. Suite 500 Summary: Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The COL4A2 test was negative. No microbleeds or cystic cavities were found. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Facebook: https://www.facebook.com/Col4A1Foundation Please Note (2015) 84:91826. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. doi: 10.1186/s12881-014-0097-2, 11. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. 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. 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. 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. doi: 10.1212/WNL.0b013e3181eee440, 28. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. In the brain, intracerebral hemorrhage is the most frequent phenotype. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. 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. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Acute urinary retention due to a novel collagen COL4A1 mutation. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Front. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 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. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. The number of genes implicated in epilepsy has grown rapidly in the past decade. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Nearly half of these participants were diagnosed with infantile spasms. Curr Opin Neurol. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 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). Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. These genes are the blueprints for two proteins that wind together like a long rope inside cells. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Dr. Madsen suggested Zeeva have an operation called a The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Jeanne M, Gould DB. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. 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). seizure activity. (2009) 73:187382. 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. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. Contact a health care provider if you have questions about your health. eCollection 2022. 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). Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. The https:// ensures that you are connecting to the 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. 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. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. doi: 10.1056/NEJMoa1707914, 6. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. doi: 10.1055/s-0031-1275343, 24. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 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). 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). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. 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. What does it mean if a disorder seems to run in my family? The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain.

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