Science. Standardized (15) familiar pedigree is showed in Figure 1. 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. The COL4A2 test was negative. doi: 10.1038/gim.2015.30, 21. (19). Clin Neurol Neurosurg. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Graefe's Arch Clin Exp Ophthalmol. doi: 10.1136/jmg.2005.035584, 15. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Epub 2022 Apr 14. 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. January 31, 2019 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). The severity of the condition varies greatly among affected individuals. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. In the brain, intracerebral hemorrhage is the most frequent phenotype. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Neuropediatrics. 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. Neurology. At least 50 individuals with this condition have been described in the scientific literature. Understanding what it has taken to get her to this point, though, is close to unimaginable. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. Cavalin M, Mine M, Philbert M, et al. Some individuals develop cysts on the kidney. MedlinePlus also links to health information from non-government Web sites. Stroke is a leading cause of death and serious long-term disability in developed nations. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Phone: 617-249-7300, Danbury, CT office These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Phone: 202-588-5700. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Muscle cramps can be spontaneous or triggered by exercise. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 2011 It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. doi: 10.1055/s-0031-1275343, 24. If we dont have a program for you now, please continue to check back with us. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. 1. COL4A1 Syndrome CADASIL 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. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 11:827. doi: 10.3389/fneur.2020.00827. Stroke. 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. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Neurology. Purpose of review: However, in people with HANAC syndrome, these aneurysms typically do not burst. National Institute of Neurological Disorders and Stroke. The .gov means its official. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Contact a health care provider if you have questions about your health. J Med Genet. Neurology. This condition causes mutations in genes that produce a specific type of collagen. Am J Med Genet. If either parent also carries the mutation, it is considered inherited. doi: 10.1016/j.matbio.2016.10.003, 23. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 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. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: (2009) 73:187382. Ann Neurol. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. Dev Med Child Neurol. NCI CPTC Antibody Characterization Program. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Danbury, CT 06810 Please enable it to take advantage of the complete set of features! Surgery may be necessary for individuals with severe cataracts. It looks like nothing was found at this location. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. In addition to porencephaly there can be other forms of damage to the brain present at birth. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). doi: 10.2214/ajr.149.2.351, 19. Hum Mol Genet. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. When these ropes are secreted, they assemble into net-like structures outside the cells. (2015) 17:84353. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: She, then, developed seizures which were controlled by valproic acid. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 128:4839. Suite 500 Please note that NORD provides this information for the benefit of the rare disease community. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Phone: 203-263-9938 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. 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. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Disease Overview. 2010;41:e513-518. This site needs JavaScript to work properly. COL4A1 is an essential component for basal membrane stability. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. 1900 Crown Colony Drive Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. (2014) 15:16. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. 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. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. doi: 10.1111/cge.12379, 13. GeneReviews. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 doi: 10.1038/gim.2014.210, 3. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. 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. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Ultrasound in utero from IV-6 (A). Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, N Engl J Med. Genet Med. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3).
