Nearly half of these participants were diagnosed with infantile spasms. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). GeneReviews. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Bull Acad Natl Med. Autosomal Dominant Brain Small Vessel Disease. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Lenses corrected for hypermetropia. and transmitted securely. It affects mainly young adults, children and more typically neonates. 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. doi: 10.1111/cge.12379, 13. TTY: (866) 411-1010 Dev Med Child Neurol. 2008 May;192(5):971-84; discussion 984-6. 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. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. What are the different ways a genetic condition can be inherited? For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. COL4A1 and COL4A2 are on Chr. 2009 Jun 25 [updated 2016 Jul 7]. 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. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. He would separate the two halves of her brain by Affected individuals may have no observable symptoms or only isolated migraines with aura. Washington, DC 20036 The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. 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). Ann Neurol. This site needs JavaScript to work properly. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. (2015) 88:46873. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. doi: 10.2214/ajr.149.2.351, 19. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 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. NORD is a registered 501(c)(3) charity organization. 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. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. (2014) 34:757. How can gene variants affect health and development? In the human genome, there are 46 chromosomes. Resource(s) for Medical Professionals and Scientists on This Disease: Cysts can also form in one or both kidneys, and the cysts may grow larger over time. This group rarely survives beyond 2 years. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 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. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Nat Methods. Cereb Circ Cogn Behav. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. IV-3 was diagnosed with ventriculomegaly in utero. Neurology. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Accessibility It is not uncommon for an unaffected parent to have a severely affected child. 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. One patient (IV-3) was treated for spasticity and seizures with valproic acid. The COL4A2 test was negative. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 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. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. government site. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Arch Ophthalmol. 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). 55 Kenosia Avenue Stroke. Childhood presentation of COL4A1 mutations. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Ultrasound in utero from IV-6 (A). [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 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). COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. (2002) 112:198202. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders.
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