Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Col4a1 mutation generates vascular abnormalities correlated with All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Neurology. 2010 Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. J Perinatol. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 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. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. National Institute of Neurological Disorders and Stroke. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Gould Syndrome is often 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. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke 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 type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). To use the sharing features on this page, please enable JavaScript. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Ultrasound in utero from IV-6 (A). Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Please enable it to take advantage of the complete set of features! The site is secure. How can gene variants affect health and development? Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. doi: 10.1016/j.matbio.2016.10.003, 23. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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. Ann Neurol. I cannot describe the feeling of seeing your child healed. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Please note that NORD provides this information for the benefit of the rare disease community. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. No use, distribution or reproduction is permitted which does not comply with these terms. seizure activity. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Dev Med Child Neurol. Matrix Biol. 8600 Rockville Pike Nearly half of these participants were diagnosed with infantile spasms. 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). 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). Stroke is a leading cause of death and serious long-term disability in developed nations. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 2011 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). Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Genet Med. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Pathology. Bull Acad Natl Med. Phone: 202-588-5700. 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. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. BMC Med Genet. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Neurologic phenotypes associated with COL4A1/2 mutations 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. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. eCollection 2021. IV-3 was diagnosed with ventriculomegaly in utero. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Figure 3. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 2010;41:e513-518. 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. 11:827. doi: 10.3389/fneur.2020.00827. Disease Overview. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. doi: 10.1001/archneur.1983.04050080067013, 17. J Neurol Sci. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Neurology. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare (2002) 112:198202. Genet Med. We provide education, advocacy, and resources for families and individuals affected. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Acute urinary retention due to a novel collagen COL4A1 mutation. (2012) 54:56974. How are genetic conditions treated or managed? Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Neurology. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. Careers. If we dont have a program for you now, please continue to check back with us. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. However, there are exceptions that depend on precisely when and where the mutation arose. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel 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 COL4A1 gene provides instructions for making one component of a protein called type IV collagen. A diagnosis can be confirmed through molecular genetic testing. Phone: 203-263-9938 For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 55 Kenosia Avenue This site needs JavaScript to work properly. Zeevas brain to treat a cyst in her brain caused by porencephaly.