The first time he came to meet us, Zeeva threw a sock at him. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 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. Front. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. It is important to discuss these concepts with a genetic counselor and understand their implications. It looks like nothing was found at this location. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. came with risks and was the hardest decision we had ever faced, yet we felt 100 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. 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. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Ann Neurol. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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: Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Accessibility The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. It is passed through families in a autosomal dominant fashion. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). (2008) 23:17. If we dont have a program for you now, please continue to check back with us. J Neurol Sci. Ann This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Phone: 202-588-5700. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 55 Kenosia Avenue The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. 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. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Eur J Paediatr Neurol. (2010) 75:7479. Science. 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). In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. NORD strives to open new assistance programs as funding allows. The risk is the same for males and females. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. my mom suggested we call Boston Childrens Hospital. 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. 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. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). doi: 10.1038/nmeth.2890, 22. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Understanding what it has taken to get her to this point, though, is close to unimaginable. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Neurology. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Bull Acad Natl Med. Matrix Biol. 1779 Massachusetts Avenue Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 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. (2008) 17:42433. Before Would you like email updates of new search results? Childhood presentation of COL4A1 mutations. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. Neurology. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Pathology. 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. Matrix Biol. 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. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 55 Kenosia Avenue cuts under the microscope. Graefe's Arch Clin Exp Ophthalmol. (1982) 40:5679. Painful muscle cramps can occur and can develop before three years of age. cutting tissue called the corpus callosum, then make some additional delicate We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. IV-3 goes to a normal school, but special schooling is required for IV-6. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Ultrasound in utero from IV-6 (A). All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Unable to load your collection due to an error, Unable to load your delegates due to an error. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. 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). She has regular physical, speech, and occupational therapy. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 2008 May;192(5):971-84; discussion 984-6. 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. doi: 10.1038/gim.2014.210, 3. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, It affects mainly young adults, children and more typically neonates. doi: 10.1056/NEJMoa1707914, 6. 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. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. doi: 10.1016/j.matbio.2016.10.003, 23. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. HHS Vulnerability Disclosure, Help 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. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Gould Syndrome is an ultra rare genetic, multi-system disorder. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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). It is ubiquitously expressed in many tissues and cell types. 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. Standardized (15) familiar pedigree is showed in Figure 1. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Migraines can occur with or without aura. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Cephalic Disorders Fact Sheet. Zeevas brain to treat a cyst in her brain caused by porencephaly. 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. 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. Neurology. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). doi: 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. doi: 10.1002/ana.23736, 4. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Maybe try a search? Type IV collagen molecules attach to each other to form complex protein networks. BMC Med Genet. COL4A1 Syndrome CADASIL 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. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. (2014) 83:122834. 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. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Doctors and researchers to bring research and medical therapeutic options to those affected. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). NCI CPTC Antibody Characterization Program. January 31, 2019 official website and that any information you provide is encrypted COL4A1/A2-related disorders are rare, genetic, multi-system disorders. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. The surgery Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. (2015) 17:84353. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 2010 Aug;41(8):e513-8. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. doi: 10.2214/ajr.149.2.351, 19. PS: wrote thi paper and performed the review of the literature under the supervision of GN. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Arch Neurol. When these ropes are secreted, they assemble into net-like structures outside the cells. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. 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). Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Berg R, Aleck A, Kaplan A. Familial porencephaly. Congenital Cephalic Disorders COL4A1/A2-related disorders are dominant genetic disorders. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. What does it mean if a disorder seems to run in my family? 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). 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. Figure 3. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families.