This is called genotype-phenotype correlation. Acute urinary retention due to a novel collagen COL4A1 mutation. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. government site. 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. Doctors and researchers to bring research and medical therapeutic options to those affected. 2010 Aug;41(8):e513-8. COL4A1 mutations in patients with sporadic late-onset intracerebral Zagaglia Selch C, Nisevic JR, et al. 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. September 2003. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. PS: wrote thi paper and performed the review of the literature under the supervision of GN. What does it mean if a disorder seems to run in my family? Contact a health care provider if you have questions about your health. This group rarely survives beyond 2 years. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. mutations: a novel genetic multisystem disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). (2008) 17:42433. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Internet. Axenfeld-Rieger anomaly and cataract can cause impaired vision. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 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. Some individuals develop cysts on the kidney. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. (2014) 83:122834. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Disease Overview. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. eCollection 2021. In the brain, intracerebral hemorrhage is the most frequent phenotype. This condition causes mutations in genes that produce a specific type of collagen. 1779 Massachusetts Avenue In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. COL4A1 Syndrome CADASIL Autosomal Dominant Familial Porencephaly Type I. Jeanne M, Gould DB. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Bone. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Gould Syndrome is a rare, genetic, multi-system disorder. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Dr. Madsen suggested Zeeva have an operation called a COL4A1 mutations as a monogenic cause of cerebral The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Federal government websites often end in .gov or .mil. 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. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. (2017) 5758:2944. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). 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. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. can also contribute. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD When these ropes are secreted, they assemble into net-like structures outside the cells. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. (19). Pediatr Neurol. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. If we dont have a program for you now, please continue to check back with us. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Please enable it to take advantage of the complete set of features! Finding the best care for Zeeva - Boston Children's Answers Please note that NORD provides this information for the benefit of the rare disease community. Bull Acad Natl Med. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. 2018;91:e2078-e2088. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. To use the sharing features on this page, please enable JavaScript. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Front Aging Neurosci. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. The size and location of cerebral cavities contributes to clinical variability. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Going from having seizures every day for six years to having no seizures is nothing short of a miracle. and transmitted securely. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Standardized (15) familiar pedigree is showed in Figure 1. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Probands' father had severe hypermetropia and bilateral cataracts. Careers. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 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. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. doi: 10.1007/s00417-014-2800-6, 12. (2020). The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 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. Mutations in the COL4A1 gene cause HANAC syndrome. Hum Mol Genet. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. NORD is a registered 501(c)(3) charity organization. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Epub 2010 Jun 17. doi: 10.1002/ajmg.10452, 18. Pathology. 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. Science. Phone: 203-263-9938 Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. 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. 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 expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 4 Both . Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Thats not to say Zeeva hasnt had to work hard since the surgery. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). He also wanted to remove a shunt that was implanted in An official website of the United States government. It is not uncommon for an unaffected parent to have a severely affected child. 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). official website and that any information you provide is encrypted Washington, DC 20036 Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Zeevas brain to treat a cyst in her brain caused by porencephaly. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. (2013) 73:4857. (No doctor had ever taken a call on their lunch break to speak with me). The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 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. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Hereditary cerebral small vessel diseases: a review. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. The risk is the same for males and females. 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. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. COL4A1-related brain small-vessel disease - MedlinePlus One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Maybe try a search? For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Neurology. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 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. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. (2007) 357:268795. 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). 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). COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. (2010). Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. These exceptions are nuanced and should be discussed with a genetic counselor. (2009) 73:187382. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Phone: 202-588-5700. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Neurol. N Engl J Med. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. What are the different ways a genetic condition can be inherited?