Treatment Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. While there are other explanations, parental mosaicism should be considered. Contact a health care provider if you have questions about your health. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Phone: 203-263-9938 Childhood presentation of COL4A1 mutations. 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. 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 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. Phone: 617-249-7300, Danbury, CT office More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. The risk is the same for males and females. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Ann Neurol. Neurology. 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. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. What are the different ways a genetic condition can be inherited? The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Curr Med Chem. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. (2014) 15:16. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. Neurol. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 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. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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. We provide education, advocacy, and resources for families and individuals affected. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. (2014) 83:122834. (2012) 54:56974. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 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. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Dev Med Child Neurol. Suite 310 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. 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. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Disclaimer. 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). There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. (2007) 357:268795. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (2015) 88:46873. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Understanding what it has taken to get her to this point, though, is close to unimaginable. It affects mainly young adults, children and more typically neonates. (2006) 43:4905. doi: 10.1212/01.WNL.0000123113.46672.68, 25. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Hereditary cerebral small vessel diseases: a review. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. doi: 10.1212/WNL.0b013e3181eee440, 28. Ophthalmological features associated with COL4A1 mutations. doi: 10.1212/WNL.0000000000000837, 20. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. 2009 Jun 25 [updated 2016 Jul 7]. Unauthorized use of these marks is strictly prohibited. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Neuropediatrics. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Neurology. Bennett RL, French KS, Resta RG, Doyle DL. 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. doi: 10.1016/j.matbio.2016.10.003, 23. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Therapies are based on the specific symptoms in each individual. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. 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). Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. What does it mean if a disorder seems to run in my family? Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. His bedside manner was incredible. doi: 10.1038/gim.2015.30, 21. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. An official website of the United States government. 1779 Massachusetts Avenue Childhood presentation of COL4A1 mutations. Epub 2010 Jun 17. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. eCollection 2022 Nov 8. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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. To use the sharing features on this page, please enable JavaScript. Neurology. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. 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. 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 COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Neurology. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Progressive cerebral atrophies in three children with COL4A1 mutations. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. He would separate the two halves of her brain by Stroke. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. (2009) 73:187382. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. 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. Firstly, it segregates within the family with the phenotype. The information on this site should not be used as a substitute for professional medical care or advice. In most people, small vessel disease in the brain does not cause symptoms. Nat Methods. 1779 Massachusetts Avenue 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). Gould Syndrome is an ultra rare genetic, multi-system disorder. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Phone: 202-588-5700. 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. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. 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. Recent findings: One patient (IV-3) was treated for spasticity and seizures with valproic acid. (2017) 5758:2944. 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/. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. In the human genome, there are 46 chromosomes. ClinVar; [VCV000389182.3]. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Cephalic Disorders Fact Sheet. The https:// ensures that you are connecting to the 1900 Crown Colony Drive Fax: 203-263-9938, Washington, DC Office It is passed through families in a autosomal dominant fashion. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. sharing sensitive information, make sure youre on a federal Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Epub 2014 Jan 5. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Washington, DC 20036 *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). (2018) 91:e207888. National Center for Biotechnology Information. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Eur J Med Genet. In the brain, intracerebral hemorrhage is the most frequent phenotype. The COL4A2 test was negative. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 128:4839. doi: doi: 10.1016/j.ejpn.2009.04.010, 27. Your support helps to ensure everyones free access to NORDs rare disease reports. COL4A1/A2-related disorders are dominant genetic disorders. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders.