Phone: 202-588-5700. (2006) 354:148996. 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. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). He smiled, caught it, and asked Zeeva if he could throw it back. (2013) 73:4857. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Gould Syndrome is an ultra rare genetic, multi-system disorder. Pathology. Jeanne M, Gould DB. At least 50 individuals with this condition have been described in the scientific literature. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Hereditary cerebral small vessel diseases: a review. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. GeneReviews. When this enzyme is elevated, it is a sign of muscle damage. 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. Before Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Surgery may be necessary for individuals with severe cataracts. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 1779 Massachusetts Avenue Danbury, CT 06810 A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. (2014) 15:16. In most people, small vessel disease in the brain does not cause symptoms. 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). Zeevas brain to treat a cyst in her brain caused by porencephaly. 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. This is called genotype-phenotype correlation. Stroke is a leading cause of death and serious long-term disability in developed nations. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. (2017) 5758:2944. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. September 2003. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 2010 Autosomal Dominant Familial Porencephaly Type I. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. What does it mean if a disorder seems to run in my family? (2005) 308:116771. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. (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). doi: 10.1212/WNL.0000000000001309, 8. J Genet Couns. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. (19). Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Gould Syndrome is a rare, genetic, multi-system disorder. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. 4 Both . 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: The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Dev Med Child Neurol. To use the sharing features on this page, please enable JavaScript. 11:827. doi: 10.3389/fneur.2020.00827. Danbury, CT 06810 Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. doi: 10.1056/NEJMoa1707914, 6. Neurology. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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). 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. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. 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. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Genet Med. Mutations in the COL4A1 gene cause HANAC syndrome. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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. 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. It is not uncommon for an unaffected parent to have a severely affected child. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). NORD is a registered 501(c)(3) charity organization. Lenses corrected for hypermetropia. The information on this site should not be used as a substitute for professional medical care or advice. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. . doi: 10.1126/science.1109418, 5. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. All authors contributed to the article and approved the submitted version. Suite 500 Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. COL4A1 is an essential component for basal membrane stability. Jeanne M, Gould DB. The retina is the light-sensitive membrane that lines the inside of the eyes. 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). (2015) 17:84353. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Still other individuals may not develop any symptoms until well into adulthood. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 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 . Please note that NORD provides this information for the benefit of the rare disease community. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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. Washington, DC 20036 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). Standardized (15) familiar pedigree is showed in Figure 1. However, there are exceptions that depend on precisely when and where the mutation arose. Curr Opin Neurol. MedlinePlus also links to health information from non-government Web sites. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Ultrasound in utero from IV-6 (A). It is passed through families in a autosomal dominant fashion. (No doctor had ever taken a call on their lunch break to speak with me). Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. COL4A1 and COL4A2 are on Chr. We provide education, advocacy, and resources for families and individuals affected. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. doi: 10.1212/01.WNL.0000123113.46672.68, 25. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Type IV collagen molecules attach to each other to form complex protein networks. Doctors and researchers to bring research and medical therapeutic options to those affected. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Unauthorized use of these marks is strictly prohibited. II-2 had a limp since childhood attributed to forceps delivery. (2017) 377:111931. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. TTY: (866) 411-1010 Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. NCI CPTC Antibody Characterization Program. ClinVar; [VCV000389182.3]. Neurology. The first time he came to meet us, Zeeva threw a sock at him. (2014) 34:757. Washington, DC 20036 While there are other explanations, parental mosaicism should be considered. (2014) 83:122834. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Prenatal clinical manifestations in individuals with COL4A1/2 variants. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. The COL4A1 and COL4A2 genes were screened in proband IV-6. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 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. The information on this site should not be used as a substitute for professional medical care or advice. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. seizure activity. Nearly half of these participants were diagnosed with infantile spasms. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 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: NORD is a registered 501(c)(3) charity organization. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Clinical Testing and Workup Am J Neuroradiol. Phone: 203-263-9938 His bedside manner was incredible. 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 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. (2008) 23:17. Would you like email updates of new search results? (2012) 54:56974. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. 2009 Jun 25 [updated 2016 Jul 7]. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Neurol. doi: 10.1212/WNL.0000000000000837, 20. 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. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Hum Mol Genet. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). 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. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Matrix Biol. Cephalic Disorders Fact Sheet. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. INTERNET What are the different ways a genetic condition can be inherited? Graefe's Arch Clin Exp Ophthalmol. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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 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. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. COL4A1 Syndrome CADASIL doi: 10.1056/NEJMoa053727, 7. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Neurol. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. Rarely, new mutations in the gene occur in people with no history of the disorder in their family.
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