Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Stroke is a leading cause of death and serious long-term disability in developed nations. 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 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. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. (2002) 112:198202. 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). The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Accessibility She also showed severe hypermetropia. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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). 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 . Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. (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). Years published: 2019. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. January 31, 2019 If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. 2008 May;192(5):971-84; discussion 984-6. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. doi: 10.1186/s12881-014-0097-2, 11. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. Bethesda, MD 20894, Web Policies It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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. 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). Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. (2004) 62:16135. What does it mean if a disorder seems to run in my family? The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. COL4A1 and COL4A2 are on Chr. What is the prognosis of a genetic condition? Individuals with HANAC syndrome also experience a variety of eye problems. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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/. 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. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Am J Med Genet A. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and 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. Neurology. Suite 310 doi: 10.1056/NEJMoa1707914, 6. Still other individuals may not develop any symptoms until well into adulthood. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. 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). COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. September 2003. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. PS: wrote thi paper and performed the review of the literature under the supervision of GN. He would separate the two halves of her brain by Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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. 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. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. doi: 10.1038/nmeth.2890, 22. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). This raises questions about what tests Liliane has a lot to be grateful for this holiday season. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 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. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). COL4A1-related brain small-vessel disease - MedlinePlus Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Washington, DC 20036 It is passed through families in a autosomal dominant fashion. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. (18) and Staals et al.
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