Neurology. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. (2017) 377:111931. 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. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 2010;41:e513-518. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 4 Both . However, there are exceptions that depend on precisely when and where the mutation arose. Prenatal clinical manifestations in individuals with COL4A1/2 variants. In the human genome, there are 46 chromosomes. At least six affected families have been described in the scientific literature. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. PS: wrote thi paper and performed the review of the literature under the supervision of GN. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. How are genetic conditions treated or managed? Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. 2011 The retina is the light-sensitive membrane that lines the inside of the eyes. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Phone: 617-249-7300, Danbury, CT office Arch Neurol. Bethesda, MD 20894, Web Policies 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 8600 Rockville Pike View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. If either parent also carries the mutation, it is considered inherited. Clin Genet. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Six alpha chains of type IV. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 1. Stroke is a leading cause of death and serious long-term disability in developed nations. Stroke. (2015) 17:84353. Curr Opin Neurol. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 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. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. 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. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. It is not uncommon for an unaffected parent to have a severely affected child. Zagaglia Selch C, Nisevic JR, et al. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Phone: 203-263-9938 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). (2010) 14:1827. 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. Arch Ophthalmol. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. doi: 10.1007/s00417-014-2800-6, 12. doi: 10.1136/jmg.2005.035584, 15. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD 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. The surgery September 2003. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Am J Neuroradiol. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Quincy, MA 02169 What is Gould Syndrome? - Gould Syndrome Foundation Pathology. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. can also contribute. Neurologic phenotypes associated with COL4A1/2 mutations The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Neurology. Epub 2014 Jan 5. Changing lives of those with rare disease. Washington, DC 20036 COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. These exceptions are nuanced and should be discussed with a genetic counselor. He was confident this would reduce or stop the Ultrasound in utero from IV-6 (A). Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. About half of people with this condition also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 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. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). NORD strives to open new assistance programs as funding allows. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Front Aging Neurosci. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. Firstly, it segregates within the family with the phenotype. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. (2015) 88:46873. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 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. (1987) 8:4216. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Mutations in the COL4A1 gene cause HANAC syndrome. 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. Type IV collagen molecules attach to each other to form complex protein networks. (2010) 75:7479. doi: 10.1212/WNL.0000000000001309, 8. doi: 10.1111/cge.12543. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). 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. 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. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. 2008 May;192(5):971-84; discussion 984-6. Neurology. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Practical approach to the diagnosis of adult-onset - BMJ 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. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. While there are other explanations, parental mosaicism should be considered. 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). How are genetic conditions treated or managed? 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). Still other individuals may not develop any symptoms until well into adulthood. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Zeevas brain to treat a cyst in her brain caused by porencephaly. What are the different ways a genetic condition can be inherited? Neurol. II-2 had a limp since childhood attributed to forceps delivery. doi: 10.1111/j.1469-8749.2011.04198.x, 26. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 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. HANAC syndrome is a rare condition, although the exact prevalence is unknown. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Phone: 203-263-9938 (2002) 112:198202. I cannot describe the feeling of seeing your child healed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. 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. doi: 10.1212/WNL.0b013e3181c3fd12, 9. official website and that any information you provide is encrypted This group rarely survives beyond 2 years. seizure activity. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. 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). doi: 10.1055/s-0031-1275343, 24. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Internet. J Neurol Sci. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Nat Methods. Hereditary cerebral small vessel diseases: a review. Bone. 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. 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). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Am J Med Genet A. Please note that NORD provides this information for the benefit of the rare disease community. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. NORD is a registered 501(c)(3) charity organization. Neurology. In the human genome, there are 46 chromosomes. (2010). Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. However, in people with HANAC syndrome, these aneurysms typically do not burst. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Bull Acad Natl Med. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). This is called genotype-phenotype correlation. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. (2006) 43:4905. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Ophthalmological features associated with COL4A1 mutations. At least 50 individuals with this condition have been described in the scientific literature. N Engl J Med. Orphanet: HANAC syndrome 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). Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Some individuals develop cysts on the kidney. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. It is important to discuss these concepts with a genetic counselor and understand their implications. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. J Perinatol. 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/. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. The severity of the condition varies greatly among affected individuals. In most people, small vessel disease in the brain does not cause symptoms. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging.
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