IV-3 and IV-6 are closely followed by a neuropediatrician (VW). A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. It affects mainly young adults, children and more typically neonates. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Your support helps to ensure everyones free access to NORDs rare disease reports. 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. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. 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. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Please note that NORD provides this information for the benefit of the rare disease community. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. The surgery (2018) 91:e207888. mutations: a novel genetic multisystem disease. Fax: 203-263-9938, Washington, DC Office Standardized (15) familiar pedigree is showed in Figure 1. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). In most cases, an affected person has one parent with the condition. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Bookshelf Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Cavalin M, Mine M, Philbert M, et al. (2002) 112:198202. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 10.1161/STROKEAHA.110.581918. An official website of the United States government. At least 50 individuals with this condition have been described in the scientific literature. 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. 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. If we dont have a program for you now, please continue to check back with us. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. mutations: a novel genetic multisystem disease. Bethesda, MD 20894, Web Policies (2014) 83:122834. 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. Probands' father had severe hypermetropia and bilateral cataracts. Am J Med Genet. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Recent findings: 11:827. doi: 10.3389/fneur.2020.00827. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Suite 500 This is called genotype-phenotype correlation. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. 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. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. In the brain, intracerebral hemorrhage is the most frequent phenotype. 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. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). There are no standardized treatment protocols or guidelines for affected individuals. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. September 2003. doi: 10.1002/ana.23736, 4. Autosomal Dominant Brain Small Vessel Disease. Phone: 203-263-9938 The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1038/gim.2015.30, 21. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Nat Methods. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Plaisier E, Ronco P. COL4A1-Related Disorders. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Neurology. Type IV collagen molecules attach to each other to form complex protein networks. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). 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. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Understanding what it has taken to get her to this point, though, is close to unimaginable. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 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. Still other individuals may not develop any symptoms until well into adulthood. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Fax: 203-263-9938, Washington, DC Office The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . 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. 2011 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. 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. Eur J Med Genet. The information on this site should not be used as a substitute for professional medical care or advice. 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. 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. 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. II-2 had a limp since childhood attributed to forceps delivery. Summary. 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. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. It is passed through families in a autosomal dominant fashion. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Clin Neurol Neurosurg. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. 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. 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. The COL4A2 test was negative. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. The risk is the same for males and females. Neurology. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. N Engl J Med. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Clin Genet. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. small vessel disease: a systematic review. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Progressive cerebral atrophies in three children with COL4A1 mutations. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 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). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 1779 Massachusetts Avenue Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. In the human genome, there are 46 chromosomes. (1987) 8:4216. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Dev Med Child Neurol. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. doi: 10.1136/jmg.2005.035584, 15. doi: 10.1212/01.WNL.0000123113.46672.68, 25. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. This group rarely survives beyond 2 years. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. doi: 10.1001/archophthalmol.2010.42, 10. (2014) 11:3612. doi: We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Purpose of review: Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. It is important to discuss these concepts with a genetic counselor and understand their implications. COL4A1/A2-related disorders are dominant genetic disorders. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. Suite 310 More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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). If either parent also carries the mutation, it is considered inherited. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Years published: 2019. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. doi: 10.1212/WNL.0000000000000837, 20. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education.